Indolizine compound and use thereof

Abstract

Provided in the present invention is an indolizine compound having a structure as represented by formula I, formula II, or formula III. The indolizine compound provided in the present invention can effectively bind to a BRD7 / BRD9 bromodomain, and has a good effect. Moreover, the indolizine compound provided in the present invention has a stable structure and a simpler synthesis method.

Description

Indazine compounds and their applications

[0001] Cross-references to related applications

[0002] This application claims the benefit of Chinese application number 2025100176011, filed on January 6, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the field of chemical and pharmaceutical technology, specifically to indazine compounds and their applications. Background Technology

[0004] Bromodomains are evolutionarily conserved modules that mediate protein-protein interactions. As readers of histone acetylation, bromodomains specifically recognize histone acetylated lysine residues, thereby affecting the transcription and translation of target genes. Abnormal function of this protein complex is associated with the development of various diseases, making bromodomain proteins a novel class of targets. Inhibitors of bromodomain proteins have significant biological implications; for example, numerous compounds have been reported to have therapeutic effects in diseases such as cancer, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.

[0005] Bromodomain proteins are named after their initial discovery in Drosophila genes. Since then, they have been found in many nuclear proteins, such as histone acetyltransferases (HATs), ATP-dependent chromatin remodeling complexes, methyltransferases, and transcriptional coactivators. The human proteome encodes 61 bromodomains, which are currently found in 46 different nuclear and cytoplasmic proteins. The bromodomain protein family can be divided into eight subfamilies based on their function. Chromatin remodeling factors are one such subfamily, including BRD7, BRD9, SMARCA2, SMARCA4, and PBRM1. These proteins are key subunits of the mammalian SWI / SNF ATP-dependent chromatin remodeling complex. They participate in multiple functions of mSWI / SNF through their ability to bind KAc via their bromodomains. These functions include promoting the assembly of the pBAF and ncBAF complexes via BRD7 and BRD9, and driving the SWI / SNF complex in the direction driven by ATP synthases in chromatin.

[0006] BRD7 / BRD9 participates in multiple signaling pathways, such as JAK / STAT, Wnt / β-catenin, and TUFT1 / AKT, and acts as an important regulator influencing gene expression, cell proliferation, and apoptosis. Furthermore, as a crucial core subunit of the SWI / SNF chromatin remodeling complex, BRD7 / BRD9 plays a vital role in assembling the pBAF / ncBAF complex and exerting its biological functions. The SWI / SNF chromatin remodeling complex is one of the most common chromatin regulators in human malignancies; malignant mutations in its subunits have been found in nearly 20% of human cancers. These mutations alter the complex's normal function, thereby affecting tumorigenesis and development. Targeting BRD7 / BRD9 proteins could provide new therapeutic strategies for diseases such as cancer and inflammation. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide indazine compounds and their applications. These compounds can effectively inhibit BRD7 / BRD9 bromodomain receptors and can be further developed into drugs for the prevention or treatment of cancer, cell proliferation disorders, inflammatory diseases, autoimmune diseases, sepsis, viral infections, or neurodegenerative diseases. To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides an indazine compound, characterized in that the indazine compound has the structure shown in Formula I:

[0009] X1 and X2 are selected from C or N.

[0010] R1 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, and 0-3 Rs. 10 Substituted amino groups.

[0011] R2 and R4 are each selected from hydrogen, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C3-C7 cycloalkyl, -COR9, 0-3 R 10 Substituted amino groups, 0-3 R groups 10 Substituted amino C1-C3 alkyl, -CONH-R 11 R9 is selected from hydroxyl and alkoxy groups; R 10 and R 11 Each of the following is selected from C1-C5 alkyl, C3-C7 cycloalkyl, benzyl, -SO2-C1-C5 alkyl, -SO2-C1-C5 alkoxy, -SO2-C6-C10 aryl substituted by one or more substituents, or 5-10 heteroaryl substituted by one or more substituents containing a carbon atom and 1-4 heteroatoms selected from N, O and S.

[0012] R3 is selected from hydrogen, aldehyde, acetyl, and -YR. 12 Where Y is selected from -CH(CH3)2- and -(CH2). n -、-CO-;R 12 Selected from hydroxyl groups, 0-3 R groups 13 A substituted amino group; a 5-10 membered heterocyclic group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; a 5-10 membered heteroaryl group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; R 13 Selected from C1-C5 alkyl groups, and selected from n = 1-5.

[0013] R5 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, -OR 14 ;R 14 Selected from hydrogen, benzyl, -SO2-C1-C5 alkyl, -CONH-R 15 ;R 15 Selected from 0-3 C1-C5 alkyl groups.

[0014] R6 is selected from hydrogen, C1-C5 alkyl groups, and -COR. 16 ;R 16 Selected from C1-C5 alkyl and C3-C7 cycloalkyl with 0-3 halogen substitutions.

[0015] R7 and R8 are selected from hydrogen and C1-C5 alkyl groups.

[0016] In one embodiment, the indazine compound has the structure shown in Formula II:

[0017] X1 is selected from C or N.

[0018] R1 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, 0-3 Rs 10 Substituted amino groups.

[0019] R2 and R4 are each selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C3-C7 cycloalkyl, -COR9, 0-3 R groups. 10 Substituted amino groups, 0-3 R groups 10 Substituted amino C1-C3 alkyl, -CONH-R 11 R9 is selected from hydroxyl and alkoxy groups; R 10 and R 11Each of the following is selected from C1-C5 alkyl, C3-C7 cycloalkyl, benzyl, -SO2-C1-C5 alkyl, -SO2-C1-C5 alkoxy, -SO2-C6-C10 aryl substituted by one or more substituents, or 5-10 heteroaryl substituted by one or more substituents containing a carbon atom and 1-4 heteroatoms selected from N, O and S.

[0020] R3 is selected from hydrogen, aldehyde, acetyl, and -YR. 12 Where Y is selected from -CH(CH3)2- and -(CH2). n -、-CO-;R 12 Selected from hydroxyl groups, 0-3 R groups 13 A substituted amino group; a 5-10 membered heterocyclic group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; a 5-10 membered heteroaryl group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; R 13 Selected from C1-C5 alkyl groups, and selected from n = 1-5.

[0021] R5 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, -OR 14 ;R 14 Selected from hydrogen, benzyl, -SO2-C1-C5 alkyl, -CONH-R 15 ;R 15 Selected from 0-3 C1-C5 alkyl groups.

[0022] R6 is selected from hydrogen, C1-C5 alkyl groups, and -COR. 16 ;R 16 Selected from C1-C5 alkyl and C3-C7 cycloalkyl.

[0023] R7 and R8 are selected from hydrogen and C1-C5 alkyl groups.

[0024] In another embodiment, the indazine compound has the structure shown in Formula III:

[0025] X1 is selected from C or N.

[0026] R1 is selected from hydrogen, C1-C5 alkoxy groups, and 0-3 R groups. 10 Substituted amino groups.

[0027] R2 and R4 are each selected from hydrogen, C1-C5 alkoxy groups, -COR9, and 0-3 R groups. 10 Substituted amino groups, 0-3 R groups 10 Substituted amino C1-C3 alkyl, -CONH-R 11 R9 is selected from hydroxyl and alkoxy groups; R 10 and R11 Each is selected from C1-C5 alkyl, C3-C7 cycloalkyl, benzyl, -SO2-C1-C5 alkyl, -SO2- and C6-C10 aryl groups substituted by one or more substituents.

[0028] R3 is selected from hydrogen, -YR 12 Where Y is selected from -CH(CH3)2- and -(CH2). n -、-CO-;R 12 Selected from hydroxyl groups, 0-3 R groups 13 A substituted amino group; a 5-10 membered heterocyclic group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; a 5-10 membered heteroaryl group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; R 13 Selected from C1-C5 alkyl groups, and selected from n being 1-5. Preferably, R 12 It can be imidazole, morpholino, pyrazol, thiazolyl, etc.

[0029] R5 is selected from hydrogen, C1-C5 alkoxy group, and -OR. 14 ;R 14 Selected from hydrogen, benzyl, -SO2-C1-C5 alkyl, -CONH-R 15 ;R 15 Selected from 0-3 C1-C5 alkyl groups.

[0030] R 16 Selected from C1-C5 alkyl and C3-C7 cycloalkyl. Preferably, R 16 It can be methyl, ethyl, isopropyl, or cyclopropyl.

[0031] R7 and R8 are selected from hydrogen and C1-C5 alkyl groups.

[0032] In a preferred embodiment, the compound of the present invention is any one of the following compounds:

[0033] 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)indene-3-yl)ethane-1-one

[0034] 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-2,5-dimethoxyphenyl)indene-3-yl)ethane-1-one

[0035] 1-(1-(2,5-dimethoxy-4-(methoxymethyl)phenyl)indolinazine-3-yl)ethyl-1-one

[0036] 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0037] 1-(1-(4-((diethylamino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0038] 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N,N-dimethylbenzamide

[0039] 1-(1-(3-amino-4-((dimethylamino)methyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0040] 1-(1-(3-(dimethylamino)-4-(hydroxymethyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0041] 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N-methylbenzamide

[0042] 1-(1-(2,5-dimethoxy-4-(morpholin-4-carbonyl)phenyl)indoleazine-3-yl)ethyl-1-one

[0043] 1-(1-(4-(2-hydroxypropyl-2-yl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0044] 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)acet-1-one

[0045] 1-(1-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0046] 1-(1-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0047] 1-(1-(2,5-dimethoxy-4-(morpholinomethyl)phenyl)inden-3-yl)ethane-1-one

[0048] 1-(1-(4-((ethyl(methyl)amino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0049] 4-(3-Acetindolazin-1-yl)-2,6-dimethoxy-N,N-dimethylbenzamide

[0050] 1-(1-(3-(dimethylamino)-4-((dimethylamine)methyl)-5-methoxyphenyl)indene-3-yl)ethane-1-one

[0051] 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)indene-3-yl)prop-1-one

[0052] 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)indene-3-yl)prop-1-one

[0053] 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-(benzyloxy)azind-3-yl)ethane-1-one

[0054] 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-hydroxy-indene-3-yl)ethane-1-one

[0055] 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-indene-7-yl dimethylcarbamate

[0056] 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-indene-7-ylmethanesulfonate

[0057] 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxyindene-3-yl)ethane-1-one

[0058] 1-(1-(4-((1H-pyrazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxyindene-3-yl)ethane-1-one

[0059] 1-(1-(2,5-dimethoxy-4-((2-thio-1,3,4-thiadiazol-3(2H)-yl)methyl)phenyl)-7-methoxy-indene-3-yl)ethane-1-one

[0060] 3-(3-acetylindololin-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide

[0061] 3-(3-acetylindololin-1-yl)-4-methoxy-N-(methylsulfonyl)benzamide

[0062] 3-(3-acetyl-inden-1-yl)-N-cyclopropyl-5-methoxybenzamide

[0063] N-(3-(3-acetylindololin-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0064] 3-(3-acetyl-inden-1-yl)-N-((4-acetylphenyl)sulfonyl)-4-methoxybenzamide

[0065] 3-(3-acetyl-inden-1-yl)-4-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide

[0066] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoate methyl ester

[0067] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide

[0068] methyl 5-(3-acetyl-inden-1-yl)-2-((dimethylamino)methyl)-4-methoxybenzoate

[0069] 3-(3-acetylindoline-1-yl)-N-cyclopropyl-4-methoxybenzamide

[0070] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid

[0071] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-((3,5-dichlorophenyl)sulfonyl)-4-methoxybenzamide

[0072] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-benzyl-4-methoxybenzamide

[0073] 2-((1H-imidazol-1-yl)methyl)-N-benzyl-5-(3-isobutyrylindolazin-1-yl)-4-methoxybenzamide

[0074] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(methylsulfonyl)benzamide

[0075] N-(3-(3-acetylinden-1-yl)-5-methoxybenzyl)benzenesulfonamide

[0076] 2-((1H-imidazol-1-yl)methyl)-N-benzyl-5-(3-(cyclopropanecarbonyl)-indene-1-yl)-4-methoxybenzamide

[0077] 1-(1-(2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0078] 1-(1-(3,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0079] 4-(3-acetyl-inden-1-yl)-2,5-dimethoxybenzaldehyde

[0080] 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0081] 1-(1-(4-(1-hydroxyethyl)-2,5-dimethoxyphenyl)indene-3-yl)ethyl-1-one

[0082] 1-(1-(4-(hydroxymethyl)-3,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0083] 4-(3-acetyl-7-methoxyindene-1-yl)-2,5-dimethoxybenzaldehyde

[0084] 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-7-methoxyindene-3-yl)ethyl-1-one

[0085] 1-(1-(4-acetyl-2,5-dimethoxyphenyl)azindene-3-yl)ethyl-1-one

[0086] methyl 4-(3-acetyl-inden-1-yl)-2,6-dimethoxybenzoate

[0087] 3-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid

[0088] N-(3-(3-acetylinden-1-yl)-4-methoxyphenyl)-3-methoxybenzenesulfonamide

[0089] N-(3-(3-acetylinden-1-yl)-4-methoxybenzyl)benzenesulfonamide

[0090] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-(4-(tert-butyl)benzyl)-4-methoxybenzamide

[0091] N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-cyanobenzenesulfonamide

[0092] N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-(methylsulfonyl)benzenesulfonamide

[0093] N-(3-(3-acetylinden-1-yl)-4-methoxyphenyl)-4-formylbenzenesulfonamide

[0094] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(3-(trifluoromethyl)benzyl)benzamide

[0095] 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-(3-(hydroxymethyl)benzyl)-4-methoxybenzamide

[0096] 3-(3-acetyl-inden-1-yl)-4-methoxy-N-(pyridin-3-ylsulfonyl)benzamide

[0097] 3-(3-acetyl-inden-1-yl)-N-((4-bromophenyl)sulfonyl)-4-methoxybenzamide

[0098] 4-Methoxy-N-(benzenesulfonyl)-3-(3-propionylindoleazine-1-yl)benzamide

[0099] 4-Methoxy-N-((4-methoxyphenyl)sulfonyl)-3-(3-propionylindoleazine-1-yl)benzamide

[0100] 3-(3-acetyl-inden-1-yl)-N-((4-bromophenyl)sulfonyl)-5-methoxybenzamide

[0101] 3-(3-acetyl-inden-1-yl)-N-((4-acetylphenyl)sulfonyl)-5-methoxybenzamide

[0102] 3-(3-acetyl-inden-1-yl)-5-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide

[0103] 3-(3-acetyl-inden-1-yl)-N-(3,5-dichlorophenyl)sulfonyl)-5-methoxybenzamide

[0104] 3-Methoxy-N-(benzenesulfonyl)-5-(3-propionylindoleazine-1-yl)benzamide

[0105] N-((4-acetylphenyl)sulfonyl)-3-methoxy-5-(3-propionylindoleazine-1-yl)benzamide

[0106] 3-(3-acetyl-inden-1-yl)-5-methoxy-N-(benzenesulfonyl)benzamide

[0107] 3-(3-acetyl-inden-1-yl)-5-methoxy-N-(methylsulfonyl)benzamide

[0108] N-(3-(3-acetylinden-1-yl)-5-methoxybenzyl)methanesulfonamide

[0109] N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0110] 2-((1H-imidazol-1-yl)methyl)-N-benzyl-4-methoxy-5-(3-neovalerylindoleazine-1-yl)benzamide

[0111] N-(3-(3-isobutylindene-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0112] N-(4-methoxy-3-(3-neovalerindolazin-1-yl)phenyl)benzenesulfonamide

[0113] N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)pyridine-2-sulfonamide

[0114] N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-formylbenzenesulfonamide

[0115] 3-(3-acetyl-8-ethylinden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0116] 3-(3-acetyl-8-isopropyl-inden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0117] 3-(3-acetyl-6-ethylinden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0118] 3-(3-acetyl-6-isopropyl-inden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0119] 1-(7-(benzyloxy)-1-(2,5-dimethoxyphenyl)azine-3-yl)ethyl-1-one

[0120] 1-(7-(benzyloxy)-1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0121] 1-(1-(pyridin-2-yl)inden-3-yl)aceto-1-one

[0122] 1-(1-(3,6-dimethoxypyridin-2-yl)azinden-3-yl)acetoone

[0123] 1-(1-(4-methoxy-3,5-dimethylphenyl)azinden-3-yl)ethyl-1-one

[0124] 1-(1-Phenylenindene-3-yl)ethyl-1-one

[0125] 1-(1-(3-(hydroxymethyl)phenyl)azine-3-yl)ethyl-1-one

[0126] 1-(1-(2-chlorophenyl)azine-3-yl)ethyl-1-one

[0127] 1-(1-(3-(trifluoromethyl)phenyl)inden-3-yl)ethyl-1-one

[0128] 1-(1-(2-methoxyphenyl)azine-3-yl)ethyl-1-one

[0129] 1-(1-(3-methoxyphenyl)azine-3-yl)ethyl-1-one

[0130] When indazine compounds have structures as shown in Formula I, II, or III, the preparation methods include routes one through four. Route one is the synthetic route for the borate ester of the indazine nucleus; route two is the synthesis of different ZA fragments; route three is a subsequent synthetic route obtained by Suzuki coupling of the borate ester of route one with a commercially available ZA fragment or by reacting the product of Suzuki coupling from the first two routes with sulfonyl chloride or sulfonamide; route four is obtained by cyclization of pyridinium salt with aromatic yne.

[0131] The specific route one for indazine-based borate esters is as follows:

[0132] The specific synthesis routes for different ZA fragments I, II, and III are as follows:

[0133] Route 3 is detailed below:

[0134] Route 4 is detailed below:

[0135] Where R1-R 17 R1-R as described in claim 1 17 They have the same range.

[0136] In Route 1, compound 4 is prepared by reacting pyridine derivative compound 3 with α-haloketone in ethyl acetate as solvent;

[0137] Preferably, compound 5 is obtained by reacting compound 4 with methyl propynate under dichloromethane and triethylamine conditions;

[0138] Preferably, compound 6 is obtained from compound 5 in methanol / tetrahydrofuran in the presence of sodium hydroxide;

[0139] Preferably, compound 7 is obtained by reacting compound 6 with N-bromosuccinimide in DMF with sodium carbonate;

[0140] Preferably, compound 8 is obtained by reacting compound 7 with potassium acetate and neopentyl glycol diboronate at 80°C for 10 h in dioxane or DMSO as solvent and PdCl2(dppf)·CH2Cl2 as catalyst.

[0141] Preferably, the compound of formula I is obtained by reacting compound 8 with barium hydroxide octahydrate and a bromobenzene derivative at 80°C for 10 h in a solvent of dioxane / water and a catalyst of PdCl2(dppf)·CH2Cl2.

[0142] In Route 2, compound 10 is obtained by reducing compound 9 in methanol with sodium borohydride or by Jones oxidation;

[0143] Preferably, compound 11 is obtained by halogenating compound 10 with PBr3 or SOCl2 in dichloromethane;

[0144] Preferably, compound 12 is obtained by nucleophilic addition or condensation of compound 11 with different amine derivatives;

[0145] Preferably, compound 14 is obtained by radical methylation of compound 13;

[0146] Preferably, compound 15 is obtained by substituting compound 14 with different derivatives;

[0147] Preferably, compound 17 is obtained by brominating compound 16 with NBS;

[0148] Preferably, compound 18 is obtained by methylating compound 17 with iodomethane;

[0149] In route three, compound 20 is obtained by reacting compound 19 with different nucleophiles under PBr3 conditions.

[0150] Preferably, compound 22 is obtained by condensation of compound 21 with different sulfonamide derivatives;

[0151] Preferably, compound 23 is obtained by condensation of compound 22 with a sulfonyl chloride derivative;

[0152] In route four, compound 24 is obtained by cyclizing aromatic alkynes and their derivatives with pyridine salt derivatives under triethylamine conditions.

[0153] 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 easily synthesized using techniques in the art and from readily available starting materials. If a substituent itself is 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.

[0154] Terminology Explanation:

[0155] As used in this invention, the terms "halogen", "halogen", etc., refer to fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

[0156] As used herein, the term "alkyl" refers to both branched and straight-chain aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C5" in "C1-C5" alkyl groups includes alkyl groups having 1, 2, 3, 4, or 5 carbon atoms arranged in a straight or branched chain. Specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, etc. "Cycloalkyl" refers to cyclic alkyl groups having a specific number of carbon atoms; for example, when "C3-C7" cycloalkyl groups are mentioned, the number of carbon atoms can be 3 to 7. Specific groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, etc.

[0157] As mentioned in this invention, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as phenyl, naphthyl, anthracene, phenanthryl, indene, and similar groups.

[0158] As used herein, the term "heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N, and S. Heteroaryl groups include monocyclic or polycyclic ring systems (such as those with 2, 3, or 4 fused rings). Any N atom cyclic in a heterocyclic group can also be oxidized to form an N-oxide. The heteroaryl groups within this definition include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thiopheneyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrroleyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, indolyl, inzolyl, quinolinyl, isoquinolinyl, purineyl, carbazoleyl, benzimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, and similar groups.

[0159] As used herein, the term "heterocyclic" or "heterocyclic group" refers to a non-aromatic heterocycle containing a carbon atom and 1-4 heteroatoms selected from N, O, and S. Heterocyclic groups can include monocyclic or polycyclic ring systems (such as those having 2, 3, or 4 fused rings) as well as spirocyclic rings. Further examples of "heterocyclic group" include, but are not limited to: azirropropyl, azirrobutyl, tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperazine, piperidinyl, and similar groups. Also included in the definition of heterocyclic alkyl groups are those moieties having one or more aromatic rings fused to a non-aromatic heterocyclic alkyl ring (e.g., having a shared bond), such as 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, benzo-1,4-dioxacyclohexyl, phthalimide, naphthalimide, and similar groups. Heterocyclic alkyl groups having one or more fused aromatic rings can be linked by either an aromatic or non-aromatic moieties.

[0160] As used herein, the term "compound" means, as is used herein, all stereoisomers, geometric isomers, tautomers, and isotopes.

[0161] The compounds of this invention can be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers can be enantiomers and diastereomers. Compounds of this invention containing asymmetrically substituted carbon atoms can be isolated into optically pure or racemic forms. The optically pure form can be prepared by resolving the racemic mixture or by using a chiral synthon or a chiral reagent.

[0162] The compounds of this invention may also include tautomer forms. New tautomer forms are generated by the exchange of single bonds and adjacent double bonds along with proton migration.

[0163] The compounds of this invention may also include all isotopic forms of atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0164] As used in this invention, the term "pharmaceutical composition" can also refer to a "composition" that can be used in subjects, particularly mammals, to treat and / or prevent the diseases or conditions described in this invention.

[0165] This invention includes the free form of compounds of Formula I, as well as their pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds described herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in its non-salt form. Pharmaceutically acceptable salts include 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 form of a specific salt of the compound can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous solution of NaOH, potassium carbonate, dilute ammonia, or sodium bicarbonate. The free form may differ somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0166] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing either 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 the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0167] 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.

[0168] 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, diethylaminoethanol, dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

[0169] Since the deprotonated acidic portion of the compound, such as the carboxyl group, can be anionic under physiological conditions, and this charge can then be balanced by the protonated or alkylated basic portion, such as the tetravalent nitrogen atom, which carries a cation, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

[0170] In a second aspect, the present invention provides a pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound of the compound described in the first aspect.

[0171] Thirdly, the present invention provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients;

[0172] The active ingredient includes at least one compound as described in the first aspect and / or at least one pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in the second aspect.

[0173] Fourthly, the present invention provides the use of the compound described in the first aspect, the pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, deuterated compound, and pharmaceutical composition described in the second aspect in the preparation of an inhibitor that degrades the BRD7 / BRD9 bromodomain protein.

[0174] Fifthly, the present invention provides the use of the compounds described in the first aspect, the pharmaceutically acceptable salts, stereoisomers, N-oxides, prodrug molecules, solvates, deuterated compounds, and pharmaceutical compositions described in the second aspect in the preparation of medicaments for the prevention or treatment of cancer, cell proliferation disorders, inflammation, autoimmune diseases, sepsis, viral infections, or neurodegenerative diseases.

[0175] Preferably, the BRD7 / BRD9 bromodomain receptor inhibitor is used to prepare a drug for treating cancer.

[0176] Preferably, the BRD7 / BRD9 bromodomain receptor inhibitor is used to prepare drugs for the treatment of acute myeloid leukemia and multiple myeloma.

[0177] Drugs prepared from BRD7 / BRD9 bromodomain receptor inhibitors, and the drug compositions thereof, can treat cancers including adrenal tumors, acoustic neuromas, acral melanomas, acral hidradenomas, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumors, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, and atypical malformations. Rod-shaped tumors, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, germ cell tumor, bone tumor, brown tumor, Burkitt lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, cementum tumor, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial tumors, dysgerminoma, embryonal carcinoma, endocrine gland tumors, endodermal sinus tumors, esophageal cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancer Germ cell tumors, choriocarcinoma of pregnancy, giant cell fibroblastoma, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, granular cell tumor, androgenetic adenomas, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancers, hemangiopericytoma, hepatoblastoma, cellular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, deadly midline carcinoma, testicular interstitial cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoepithelioma, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, malt lymphoma, malignant tumors Fibrohistocytoma, malignant peripheral nerve sheath tumor, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic cell carcinoma, mixed Müllerian tumor, myxoid tumor, multiple myeloma, muscle tissue tumor, mycosis myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neuroblastoma, neurofibroma, ocular cancer, eosinophilic, optic nerve sheath meningioma, oral cancer, ovarian cancer, papillary thyroid carcinoma, paraganglioma, pineal cell tumor, pituitary cell tumor, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma.Peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyosarcoma, rectal cancer, seminoma, trophoblastic tumor, small round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, spinal cord tumor, marginal zone lymphoma of the spleen, squamous cell carcinoma, synovial sarcoma, small intestinal cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, urogenital cancer, uterine cancer, verrucous carcinoma, optic nerve glioma, vulvar cancer or vaginal cancer, etc.

[0178] The pharmaceutical compositions prepared from BRD7 / BRD9 bromodomain receptor inhibitors are suitable for various routes of administration, typical but not limiting examples of which include: oral, buccal, inhalation, sublingual, rectal, vaginal, intracisional or intrathecal, via lumbar puncture, transurethral, ​​transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implantation), etc. The pharmaceutical compositions of the present invention may be in liquid, semi-liquid, or solid form, formulated in a manner suitable for the route of administration used. The compositions of the present invention may be administered via the following routes of administration: oral, parenteral, intramembranous, intravenous, transdermal, sublingual, intramuscular, rectal, oral, intranasal, liposome, etc. Orally administered pharmaceutical compositions may be solid, gel, or liquid. Examples of solid dosage forms include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents, etc. Examples of adhesives include, but are not limited to, microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, and stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, and dicalcium phosphate; examples of glidants include, but are not limited to, silica; examples of disintegrants include, but are not limited to, croscarmellose sodium, starch glycolate sodium, alginate, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose. The pharmaceutical compositions of the present invention are generally administered parenterally, primarily by injection, including subcutaneous, intramuscular, or intravenous injection. Injectable formulations can be prepared...

[0179] Any conventional form, such as a liquid solution or suspension, a solid form suitable for dissolving or suspending in a liquid prior to injection, or an emulsion. Examples of pharmaceutically acceptable carriers that can be used in the injectable formulations of this invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's solution injection, isotonic glucose injection, sterile water injection, and glucose and lactated Ringer's solution injection; examples of non-aqueous carriers include plant-derived fixed oils, cottonseed oil, corn oil, sesame oil, and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; and examples of buffers include phosphates and citrates.

[0180] The pharmaceutical composition of the present invention can also be prepared into a sterile lyophilized powder for injection by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, then sterilely filtering the solution under standard conditions known to those skilled in the art, followed by freeze-drying to obtain the desired formulation.

[0181] Compared with the prior art, the present invention has the following beneficial effects: the indazine compounds provided by the present invention can effectively bind to the BRD7 / BRD9 bromine domain, and have an inhibition rate of more than 70% against acute myeloid leukemia cells, showing good efficacy, and have good selectivity for other bromine domain family proteins; moreover, the indazine compounds provided by the present invention have stable structures and simpler synthesis methods. Detailed Implementation

[0182] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be considered as specific limitations thereof. In the following embodiments of the present invention, the compounds obtained in each embodiment are numbered.

[0183] The structures of the compounds in Examples 1-97 and Comparative Examples 1 and 2 are shown in Table 1.

[0184] Table 1 Comparative Examples and Embodiments

[0185] Example 1

[0186] Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)-indene-3-yl)ethane-1-one

[0187] Step 1: Synthesis of 1-(2-Oxypropyl)pyridine ammonium chloride

[0188] Pyridine (79.1g, 10mL, 126.4mmol, 1eq) was dissolved in 400mL of ethyl acetate, and chloroacetone (92.5g, 12.5mL, 151.68mmol, 1.2eq) was added. The mixture was reacted overnight at 70°C. After the reaction was completed by TLC, the mixture was cooled to room temperature and filtered to obtain a white precipitate. The precipitate was washed with ethyl acetate to give a white solid product, 1-(2-oxypropyl)pyridine ammonium chloride (171.6g, 15g, 87.4mmol, 69%). 1 H NMR (500MHz, D2O): δ8.72(d,J=6.2Hz,2H,2×Ar-H),8.70–8.65(m,1H,Ar-H),8.18(t,J=6.9Hz,2H,2×Ar-H),3.39(s,1H,CH2),2.48(s,3H,CH3).

[0189] Step 2: Synthesis of methyl 3-acetylindoleazine-1-carboxylate

[0190] Dissolve 1-(2-oxopropyl)pyridine ammonium chloride (171.62 g, 87.4 mmol, 1 eq) in 300 mL of dichloromethane (DCM). Under ice bath conditions, slowly add triethylamine (101.19 g, 18.22 mL, 131.1 mmol, 1.5 eq). After the system turns yellow, slowly add methyl propargylate (84.07 g, 11.66 mL, 131.1 mmol, 1.5 eq). Add a small amount of methanol until the system becomes clear. React overnight at room temperature. After the reaction is complete, concentrate under vacuum to remove the solvent, extract with ethyl acetate / dilute hydrochloric acid, back-extract once, dry to anhydrous sodium sulfate, and then perform column chromatography (petroleum ether:ethyl acetate = 10:1) to give a pale yellow solid product, methyl 3-acetylindolazine-1-carboxylate (217.22 g, 11.2 g, 51.56 mmol, 59%). 1 H NMR (500MHz, DMSO-d6): δ9.78 (d, J=7.0Hz, 1H, Ar-H), 8.26 (d, J=8.9Hz, 1H, Ar-H), 8.15 (s, 1H, A r-H),7.60–7.53(m,1H,Ar-H),7.24(t,J=6.9Hz,1H,Ar-H),3.85(s,3H,OCH3),2.56(s,3H,CH3).

[0191] Step 3: Synthesis of 3-acetylindoleazine-1-carboxylic acid

[0192] Methyl 3-acetylindoleazine-1-carboxylic acid (217.22 g, 11.20 g, 51.56 mmol, 1 eq) was dissolved in 600 mL of a methanol / tetrahydrofuran mixture. NaOH (40 g, 20.6 g, 515.6 mmol, 10 eq) was dissolved in 200 mL of water. The sodium hydroxide solution was slowly added to the 2-5a system, and the reaction was carried out at 60 °C for 4 hours. After the reaction was completed, the solution was concentrated, extracted with DCM to remove impurities, and acidified with 4 M HCl to pH 1. The solid was filtered, washed with water and methanol, and concentrated under vacuum at 70 °C to obtain a pale yellow solid product, 3-acetylindoleazine-1-carboxylic acid (203.20 g, 9.8 g, 48.23 mmol, 93%). 1 H NMR (500MHz, DMSO-d6): δ9.76 (d, J=7.0Hz, 1H, Ar-H), 8.36 (d, J=8.9Hz, 1H, Ar-H), 8.0 7(s,1H,Ar-H),7.52–7.42(m,1H,Ar-H),7.16(t,J=6.5Hz,1H,Ar-H),2.54(s,3H,CH3).

[0193] Step 4: Synthesis of 1-(1-bromoindol-3-yl)ethyl-1-one

[0194] 3-Acetylindolazine-1-carboxylic acid (203.20 g, 5.00 g, 24.60 mmol, 1 eq), Na₂CO₃ (104.04 g, 7.68 g, 73.82 mmol, 3 eq), and N-bromosuccinimide (NBS) (177.98 g, 8.76 g, 49.21 mmol, 2 eq) were dissolved in 200 mL of N,N-dimethylformamide (DMF) and reacted at room temperature for 1 h. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated NaCl solution, back-extracted once, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 20:1) to give a white solid product, 1-(1-bromoindol-3-yl)ethyl-1-one (238.07 g, 3.8 g, 15.96 mmol, 76%). 1 H NMR (500MHz, DMSO-d6): δ9.73 (d, J=7.1Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.62 (d, J=8.9Hz, 1H, Ar-H), 7.38 (dd, J=8.3, 7.4Hz, 1H, Ar-H), 7.11 (t, J=6.9Hz, 1H, Ar-H), 2.50 (s, 3H, CH3).

[0195] Step 5: Synthesis of 1-(1-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)indolazin-3-yl)acet-1-one

[0196] Take 1-(1-bromoindol-3-yl)ethyl-1-one (238.07 g, 2.00 g, 8.40 mmol, 1 eq), neopentyl glycol diboronate (225.89 g, 3.79 g, 16.80 mmol, 2 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (PdCl2(dppf)·CH2Cl2) (810.59 mg, 136.19 mg, 0.168 mmol, 2 mol%), and potassium acetate (98.14 g, 2.47 g, 25.20 mmol, 3 eq) and place them in a double-necked flask. Under nitrogen protection, after purging with an oil pump, add anhydrous dioxane and react at 70°C overnight. After the reaction was completed, the mixture was concentrated under vacuum, extracted with ethyl acetate / saturated NaCl solution, back-extracted with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether: ethyl acetate = 40:1) to give a white solid product 1-(1-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)indolazin-3-yl)ethyl-1-one (271.12 g, 0.95 g, 3.5 mmol, 42%).

[0197] 1 H NMR (500MHz, CDCl3): δ9.85 (d, J=7.2Hz, 1H, Ar-H), 7.52 (d, J=8.9Hz, 1H, Ar-H), 7.15–7.09 (m, 1H, Ar-H), 6.87 (t,J=6.9Hz,1H,Ar-H),6.50(d,J=4.6Hz,1H,Ar-H),3.65(s,4H,2×CH2),2.56(s,3H,CH3),0.98(s,6H,2×CH3).

[0198] Step 6: Synthesis of 5-bromo-2-(chloromethyl)-1,3-dimethoxybenzene

[0199] Dissolve (4-bromo-2,6-dimethoxyphenyl)methanol (247.09 g, 3.00 g, 12.14 mmol, 1 eq) in dichloromethane. Add thionyl chloride (118.97 g, 8.8 mL, 121.41 mmol, 10 eq) under ice bath conditions, and gradually raise the temperature to room temperature and react overnight. After the reaction is complete, concentrate under vacuum to remove the solvent. After evacuating under vacuum for 30 minutes, extract with ethyl acetate / saturated NaHCO3 solution, back-extract once with dichloromethane, dry with anhydrous sodium sulfate, and then evaporate to dryness to obtain the crude product 5-bromo-2-(chloromethyl)-1,3-dimethoxyphenyl. 1 H NMR (400MHz, CDCl3): δ6.70 (s, 2H, 2×Ar-H), 4.69 (s, 2H, CH2), 3.86 (s, 6H, 2×OCH3).

[0200] Step 7: Synthesis of 1-(4-bromo-2,6-dimethoxybenzyl)-1H-imidazolium

[0201] 5-Bromo-2-(chloromethyl)-1,3-dimethoxybenzene (265.53 g, 1.00 g, 3.77 mmol, 1 eq) and imidazole (68.08 g, 2.56 g, 37.7 mmol, 10 eq) were dissolved in dichloromethane / methanol and reacted overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum concentration, extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 1:1) to give 1-(4-bromo-2,6-dimethoxybenzyl)-1H-imidazolium (297.15 mg, 521 mg, 1.75 mmol, 47%). 1 H NMR (400MHz, CDCl3): δ7.54(s,1H,Ar-H),6.99(s,1H,Ar-H),6.91(s,2H,2×Ar-H),6.80(s,1H,Ar-H),5.01(s,2H,CH2),3.85(s,6H,2×OCH3).

[0202] Step 8: Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)-indene-3-yl)ethane-1-one

[0203] Dissolve 1-(4-bromo-2,6-dimethoxybenzyl)-1H-imidazolium (297.15 mg, 100 mg, 0.34 mmol, 1 eq), 1-(1-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)indolazin-3-yl)aceto-1-one (271.12 mg, 150 mg, 0.55 mmol, 1.6 eq), Ba(OH)2·8H2O (315.46 mg, 429 mg, 1.36 mmol, 4 eq), and PdCl2(dppf)·CH2Cl2 (810.59 mg, 5.51 mg, 0.0068 mmol, 2 mol%) in a mixed solvent of dioxane / tetrahydrofuran / water = 3:2:1. Under nitrogen protection and evacuation for 10 min, react overnight at 80 °C. After the reaction was completed, the mixture was concentrated under vacuum, extracted with ethyl acetate / saturated brine, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether: ethyl acetate = 1:1) to give 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)indene-3-yl)ethane-1-one (375.43 mg, 70.2 mg, 0.187 mmol, 55%). 1H NMR (500MHz, DMSO): δ9.81(d,J=6.9Hz,1H,Ar-H),8.08(s,H,Ar-H),8.06(s,H,Ar-H),7.60(s,1H,Ar-H),7.34(t,J=7.8Hz,1H,Ar-H),7.09(t ,J=6.9Hz,1H,Ar-H),7.06(s,1H,Ar-H),6.93(s,2H,2×Ar-H),6.83(s,1H,Ar-H),5.10(s,2H,CH2),3.95(s,6H,2×OCH3),2.57(s,3H,COCH3).

[0204] Example 2

[0205] Synthesis of 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-2,5-dimethoxyphenyl) inden-3-yl)ethane-1-one

[0206] Step 1: Synthesis of 1-(4-bromo-2,5-dimethoxybenzyl)azacyclobutane-3-ol

[0207] The synthesis method is the same as in Example 1, with a yield of 50%. 1 H NMR (500MHz, DMSO): δ7.14(s,1H,Ar-H),6.97(s,1H,Ar-H),5.33(s,1H,OH),4.23–4.14(m,1H,CH),3.77(s ,3H,OCH3),3.73(s,3H,OCH3),3.53(t,J=6.5Hz,2H,CH2),3.47(s,2H,Ar-CH2),2.76(t,J=6.7Hz,2H,CH2).

[0208] Step 2: Synthesis of 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-2,5-dimethoxyphenyl)-indene-3-yl)ethane-1-one

[0209] The synthesis method is the same as in Example 12, with a yield of 42%. 1H NMR (500MHz, DMSO): δ9.78 (d, J=7.0Hz, 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.57 (d, J=8.9H z,1H,Ar-H),7.30–7.21(m,1H,Ar-H),7.05(t,J=7.0Hz,1H,Ar-H),7.02(s,1H,Ar-H) ,6.97(s,1H,Ar-H),4.26–4.19(m,1H,Ar-H),3.78(s,3H,OCH3),3.71(s,3H,OCH3),3 .60(m,2H,CH2),3.59(s,2H,Ar-CH2),2.82(t,J=6.6Hz,2H,CH2),2.54(s,3H,COCH3).

[0210] Example 3

[0211] Synthesis of 1-(1-(2,5-dimethoxy-4-(methoxymethyl)phenyl)indolinazin-3-yl)ethyl-1-one

[0212] Step 1: Synthesis of 1-bromo-2,5-dimethoxy-4-(methoxymethyl)benzene

[0213] (4-Bromo-2,5-dimethoxyphenyl)methanol (247.09 mg, 100 mg, 0.40 mmol, 1 eq) and NaH (24 mg, 19.43 mg, 0.81 mmol, 2 eq) were added to a tetrahydrofuran solution under nitrogen protection in an ice bath and stirred for 20 minutes. CH3I (141.94 mg, 0.05 mL, 0.81 mmol, 2 eq) was then slowly added, and the reaction was carried out at room temperature for 3 hours. After the reaction was complete, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated NaCl solution and back-extracted once with dichloromethane to give crude product 2-31 (261.12 mg, 95 mg, 0.36 mmol, 90%). 1 H NMR (500MHz, CDCl3): δ7.05(s,1H,Ar-H),6.99(s,1H,Ar-H),4.44(s,2H,CH2),3.87(s,3H,Ar-OCH3),3.79(s,3H,Ar-OCH3),3.43(s,3H,OCH3).

[0214] Step 2: Synthesis of 1-(1-(2,5-dimethoxy-4-(methoxymethyl)phenyl)indolinazin-3-yl)ethyl-1-one

[0215] The synthesis method is the same as in Example 1, with a yield of 49%. 1H NMR(500MHz,CDCl3)δ9.89(d,J=7.1Hz,1H,Ar-H),7.64(s,1H,Ar-H),7.56(d,J=8.9Hz,1H,Ar-H),7.16–7.11(m,1H,Ar-H),7.10(s,1H,Ar-H),6.9 5(s,1H,Ar-H),6.88(t,J=6.8Hz,1H,Ar-H),4.56(s,2H,CH2),3.84(s,3H,Ar-OCH3),3.80(s,3H,Ar-OCH3),3.49(s,3H,OCH3),2.59(s,3H,COCH3).

[0216] Example 4

[0217] Synthesis of 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)acet-1-one

[0218] Step 1: Synthesis of 1-(4-bromo-2,6-dimethoxybenzyl)azacyclobutane-3-ol

[0219] The synthesis method is the same as in Example 14, with a yield of 60%. 1 H NMR (500MHz, CDCl3): δ6.98(s,2H,2×Ar-H),4.34(m,1H,CH),3.80(s,6H,2×OCH3),3.69(s,2H,Ar-CH2),3.64(m,2H,CH2),3.12(m,2H,CH2).

[0220] Step 2: Synthesis of 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)acet-1-one

[0221] The synthesis method is the same as in Example 9, with a yield of 65%. 1 H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.84(d,J=8.9Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.24–7.16(m,1H,Ar-H),6.92(t,J=6.9Hz,1H,Ar-H),6 .73(s,2H,2×Ar-H),4.44–4.35(m,1H,CH),3.89(s,6H,2×OCH3),3.83(s,2H,A r-CH2),3.73(t,J=7.3Hz,2H,CH2),3.29–3.15(m,2H,CH2),2.62(s,3H,CH3).

[0222] Example 5

[0223] Synthesis of 1-(1-(4-((diethylamino)methyl)-3,5-dimethoxyphenyl)indolinazin-3-yl)ethyl-1-one

[0224] The synthesis method is the same as in Example 16, with a yield of 59%. 1 H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.84(d,J=8.9Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.24–7.14(m,1H,Ar-H),6.91(t,J=6.9 Hz,1H,Ar-H),6.72(s,2H,2×Ar-H),3.88(s,6H,2×OCH3),3.68(s,2H,CH2),2.65–2.59(m,7H,COCH3,2×CH2),1.11(t,J=7.1Hz,6H,2×CH3).

[0225] Example 6

[0226] Synthesis of 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N,N-dimethylbenzamide

[0227] Step 1: Synthesis of 4-bromo-2,5-dimethoxy-N,N-dimethylbenzamide

[0228] The synthesis method is the same as in Example 9, with a yield of 68%.

[0229] (500MHz, CDCl3): δ7.09(s,1H,Ar-H),6.81(s,1H,Ar-H),3.82(s,3H,OCH3),3.76(s,3H,OCH3),3.07(s,3H,NCH3),2.83(s,3H,NCH3).

[0230] Step 2, Synthesis of 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N,N-dimethylbenzamide

[0231] The synthesis method is the same as in Example 1, with a yield of 30%. 1H NMR (500MHz, CDCl3): δ7.63(s,1H,Ar-H),7.54(d,J=8.9Hz,1H,Ar-H),7.20–7.13(m,1H,Ar-H),6.97(s,1H,Ar-H),6.95(s,1H,Ar -H),6.91(t,J=6.8Hz,1H,Ar-H),3.84(s,3H,OCH3),3.78(s,3H,OCH3),3.16(s,3H,NCH3),2.96(s,3H,NCH3),2.60(s,3H,COCH3).

[0232] Example 7

[0233] Synthesis of 1-(1-(3-amino-4-((dimethylamino)methyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0234] Step 1: Synthesis of 1-(4-bromo-2-fluoro-6-nitrophenyl)-N,N-dimethylformamide

[0235] 5-Bromo-1-fluoro-2-methyl-3-nitrobenzene (243.23 g, 4.27 mmol, 1 eq), BPO (243.23 g, 52 mg, 0.21 mmol, 0.05 eq), and NBS (177.98 g, 8.55 mmol, 2 eq) were dissolved in acetonitrile and refluxed overnight. After the reaction was stopped, the solvent was removed by vacuum concentration, extracted with ethyl acetate / saturated Na₂S₂O₃ solution, back-extracted with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under vacuum before proceeding directly to the next step. The concentrated system was dissolved in methanol, and 5 mL of dimethylamino alcohol solution was added. The reaction was carried out at room temperature for 3 hours. After the reaction was complete, the solvent was removed by vacuum concentration, and the product was extracted with ethyl acetate / dilute hydrochloric acid. The ethyl acetate layer was back-extracted once with water, and the pH of the aqueous layer was adjusted to alkaline with 4M sodium hydroxide solution. The product was then extracted with ethyl acetate, back-extracted once with dichloromethane, and concentrated under vacuum to obtain 1-(4-bromo-2-fluoro-6-nitrophenyl)-N,N-dimethylformamide (288.14 mg, 310 mmol, 1.08 mmol, 25%). 1 H NMR (400MHz, CDCl3): δ7.74(s,1H,Ar-H),7.47(dd,J=8.6,1.6Hz,1H,Ar-H),3.74(s,2H,CH2),2.22(s,6H,2×NCH3).

[0236] Step 2: Synthesis of 1-(4-bromo-2-methoxy-6-nitrophenyl)-N,N-dimethylformamide

[0237] The synthesis method is the same as in Example 8, with a yield of 15%. 1H NMR (400MHz, CDCl3): δ7.46(s,1H,Ar-H),7.19(s,1H,Ar-H),3.91(s,3H,OCH3),3.75(s,2H,CH2),2.23(s,6H,2×NCH3).

[0238] Step 3: Synthesis of 5-bromo-2-((dimethylamino)methyl)-3-methoxyaniline

[0239] Iron powder (55.85 mg, 193 mg, 3.46 mmol, 5 eq) and NH4Cl (53.49 mg, 37 mg, 0.69 mmol, 1 eq) dissolved in 2 mL of water were added to a single-necked flask. The mixture was heated to 60 °C, and after the system turned yellow, 2-35 mg (289.13 mg, 200 mg, 0.69 mmol, 1 eq) dissolved in ethanol was slowly added to the system. After the reaction was complete, the solid was filtered off, concentrated under vacuum to remove the solvent, extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography. The product 5-bromo-2-((dimethylamino)methyl)-3-methoxyaniline (259.15 mg, 80 mg, 0.31 mmol, 45%) was obtained by petroleum ether:ethyl acetate = 2:1 (1% triethylamine). 1 H NMR (400MHz, CDCl3): δ6.46 (d, J=1.4Hz, 1H, Ar-H), 6.42 (d, J=1.4Hz, 1H, Ar-H) ,4.90(brs,2H,NH2),3.75(s,3H,OCH3),3.50(s,2H,CH2),2.22(s,6H,2×NCH3).

[0240] Step 4: Synthesis of 1-(1-(3-amino-4-((dimethylamino)methyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0241] The synthesis method is the same as in Example 1, with a yield of 70%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.1Hz,1H,Ar-H),7.99(d,J=9.0Hz,1H,Ar-H),7.94(s,1H,Ar-H),7.35–7.27(m,1H,Ar-H),7.07(t,J=6.7Hz, 1H,Ar-H),6.64(s,1H,Ar-H),6.50(s,1H,Ar-H),5.38(s,2H,NH2),3.80(s,3H,OCH3),3.40(s,2H,CH2),2.56(s,3H,COCH3),2.14(s,6H,2×NCH3).

[0242] Example 8

[0243] Synthesis of 1-(1-(3-(dimethylamino)-4-(hydroxymethyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0244] Step 1: Synthesis of 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde

[0245] 4-Bromo-2,6-difluorobenzaldehyde (221.0 g, 9.05 mmol, 1 eq) was dissolved in 10 mL of DMF, and KOH (56.11 g, 1.01 g, 18.1 mmol, 2 eq) was dissolved in 15 mL of water and slowly added dropwise to the system. The reaction was carried out at 60 °C for 2 hours. After the reaction was completed, the mixture was diluted with a large amount of ethyl acetate, extracted with ethyl acetate / saturated brine, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 10:1) to give the product 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde (246.08 g, 1.1 g, 4.47 mmol, 49%). 1 H NMR (400MHz, DMSO-d6): δ10.30(s,1H,CHO),7.05(s,1H,Ar-H),6.99-6.96(m,1H,Ar-H),2.87(s,6H,2×NCH3).

[0246] Step 2: Synthesis of 4-bromo-2-(dimethylamino)-6-methoxybenzaldehyde

[0247] 4-Bromo-2-(dimethylamino)-6-fluorobenzaldehyde (246.08 g, 1.1 g, 4.47 mmol, 1 eq) was dissolved in methanol, and sodium methoxide solution (54.02 mL, 1.65 mL, 8.94 mmol, 2 eq) was added. The mixture was sealed and reacted overnight at 66°C. After the reaction was complete, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated brine, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 30:1) to give the product 4-bromo-2-(dimethylamino)-6-methoxybenzaldehyde (258.12 g, 600 mg, 2.32 mmol, 52%). 1 H NMR (500MHz, CDCl3): δ10.25(s,1H,CHO),6.73(s,1H,Ar-H),6.55(d,J=1Hz,1H,Ar-H),3.87(s,1H,CH3),2.89(s,6H,2×NCH3).

[0248] Step 3, (4-bromo-2-(dimethylamino)-6-methoxyphenyl)methanol

[0249] The synthesis method is the same as in Example 19, with a yield of 88%.1 H NMR (500MHz, DMSO-d6): δ6.84 (d, J=1.5Hz, 1H, Ar-H), 6.78 (d, J=1.5Hz, 1H, Ar-H), 4.66 (t, J=0.5Hz, 1H, OH), 4.46 (d, J=5.5Hz, 2H, CH2), 2.69 (s, 6H, 2×NCH3).

[0250] Step 4: Synthesis of 1-(1-(3-(dimethylamino)-4-(hydroxymethyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0251] The synthesis method is the same as in Example 1, with a yield of 59%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.1Hz,1H,Ar-H),8.03(s,1H,Ar-H),7.99(d,J=9.0Hz,1H,Ar-H),7.37–7.32(m,1H,Ar-H),7.08(t, J=6.8Hz,1H,Ar-H),6.92(s,2H,2×Ar-H),4.66(s,1H,OH),4.59(s,2H,CH2),3.87(s,3H,OCH3),2.78(s,6H,2×NCH3),2.58(s,3H,CH3).

[0252] Example 9

[0253] Synthesis of 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N-methylbenzamide

[0254] Step 1: Synthesis of 4-bromo-2,5-dimethoxybenzoic acid

[0255] 4-Bromo-2,5-dimethoxybenzaldehyde (245.07 g, 4.08 mmol, 1 eq) was dissolved in acetone, and 4 mL of Jones' reagent was slowly added dropwise under ice bath conditions. The mixture was then allowed to react at room temperature for 2 h. After the reaction was complete, the residue was filtered, and the filtrate was concentrated under vacuum. The filtrate was extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 2:1) to give a white solid product, 4-bromo-2,5-dimethoxybenzoic acid (261.07 g, 0.72 g, 2.76 mmol, 68%). 1 H NMR (400MHz, CDCl3): δ10.67(br s,1H,COOH),7.67(s,1H,Ar-H),7.28(s,1H,Ar-H),4.04(s,3H,OCH3),3.91(s,3H,OCH3).

[0256] Step 2: Synthesis of 4-bromo-2,5-dimethoxy-N-methylbenzamide

[0257] Dissolve 4-bromo-2,5-dimethoxybenzoic acid (261.07 mg, 150 mg, 0.57 mmol, 1 eq) in dichloromethane, add thionyl chloride (118.97 mL, 5.74 mmol, 10 eq), and reflux for 2 hours. After the reaction was complete, thionyl chloride was removed by vacuum concentration. K2CO3 (138.21 mg, 158.82 mg, 1.15 mmol, 2 eq) and methylamine hydrochloride (67.52 mg, 58.2 mg, 0.86 mmol, 1.5 eq) were added and dissolved in tetrahydrofuran. The reaction was carried out at room temperature for 5 hours. After the reaction was complete, the residue was filtered. The filtrate was concentrated under vacuum, extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether: ethyl acetate = 2:1) to give the product 4-bromo-2,5-dimethoxy-N-methylbenzamide (274.11 mg, 70 mg, 0.26 mmol, 44%). 1 H NMR (500MHz, DMSO-d6): δ8.16(d,J=4.1Hz,1H,CONH),7.45(s,1H,Ar-H),7.38( s,1H,Ar-H),3.86(s,3H,OCH3),3.81(s,3H,OCH3),2.79(d,J=4.6Hz,3H,NCH3).

[0258] Step 3: Synthesis of 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N-methylbenzamide

[0259] The synthesis method is the same as in Example 1, with a yield of 32%. 1 H NMR (500MHz, DMSO-d6): δ9.80(d,J=6.8Hz,1H,Ar-H),8.22(s,1H,CONH),7.92(s,1H,Ar-H),7.62(d,J=8.7Hz,1H,Ar-H),7.57(s,1H,Ar-H),7.30( t,J=7.5Hz,1H,Ar-H),7.17(s,1H,Ar-H),7.08(s,1H,Ar-H),3.92(s,3H,OCH3),3.76(s,3H,OCH3),2.85(d,J=3.2Hz,3H,NCH3),2.56(s,3H,CH3).

[0260] Example 10

[0261] Synthesis of 1-(1-(2,5-dimethoxy-4-(morpholin-4-carbonyl)phenyl)indoleazine-3-yl)ethyl-1-one

[0262] Step 1: Synthesis of 4-bromo-2,5-dimethoxybenzoic acid

[0263] The synthesis method is the same as in Example 9, with a yield of 68%. 1 H NMR (400MHz, CDCl3): δ10.67(br s,1H,COOH),7.67(s,1H,Ar-H),7.28(s,1H,Ar-H),4.04(s,3H,OCH3),3.91(s,3H,OCH3).

[0264] Step 2: Synthesis of (4-bromo-2,5-dimethoxyphenyl)(morpholino)methyl ketone

[0265] The synthesis method is the same as in Example 9, with a yield of 65%. 1 H NMR (500MHz, DMSO-d6): δ7.32(s,1H,Ar-H),6.98(s,1H,Ar-H),3.79(s,3H,OCH3) ,3.77(s,3H,OCH3),3.66–3.56(m,4H,2×CH2),3.51(s,2H,CH2),3.13(s,2H,CH2).

[0266] Step 3: Synthesis of 1-(1-(2,5-dimethoxy-4-(morpholin-4-carbonyl)phenyl)indoleazine-3-yl)ethyl-1-one

[0267] The synthesis method is the same as in Example 9, with a yield of 30%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.0Hz,1H,Ar-H),7.88(s,1H,Ar-H),7.61(d,J=8.9Hz,1H,Ar-H),7.29(t,J=7.8Hz,1H,Ar-H),7.11(s,1H,Ar-H),7.07 (t,J=6.9Hz,1H,Ar-H),6.99(s,1H,Ar-H),3.82(s,3H,OCH3),3.73(s,3H,OCH 3),3.66(s,4H,2×CH2),3.57(s,2H,CH2),3.24(s,2H,CH2),2.55(s,3H,CH3).

[0268] Example 11

[0269] Synthesis of 1-(1-(4-(2-hydroxypropyl-2-yl)-2,5-dimethoxyphenyl)indoleazin-3-yl)ethyl-1-one

[0270] Step 1, 2-(4-bromo-2,5-dimethoxyphenyl)prop-2-ol

[0271] Dissolve 1-(4-bromo-2,5-dimethoxyphenyl)ethyl-1-one (259.10, 100 mg, 0.38 mmol, 1 eq) in tetrahydrofuran. Under nitrogen protection, slowly add methyl magnesium bromide (119.24, 0.02 mL, 0.58 mmol, 1.5 eq) in an ice bath, and slowly raise the temperature to room temperature for 6 hours. After the reaction is complete, quench with NH4Cl, concentrate under vacuum to remove the solvent, extract with ethyl acetate / saturated NaCl solution, and back-extract once with dichloromethane to give the crude product 2-(4-bromo-2,5-dimethoxyphenyl)prop-2-ol (275.14, 68 mg, 0.25 mmol, 64%). 1 H NMR (500MHz, DMSO-d6): δ7.35(s,1H,Ar-H),7.14(s,1H,Ar-H),5.15(s,1H,OH),3.77(s,1H,OCH3),3.75(s,1H,OCH3),1.45(s,6H,2×CH3).

[0272] Step 2: Synthesis of 1-(1-(4-(2-hydroxypropyl-2-yl)-2,5-dimethoxyphenyl)indoleazin-3-yl)ethyl-1-one

[0273] The synthesis method is the same as in Example 1, with a yield of 59%. 1 H NMR (500MHz, CDCl3): δ9.90(d,J=7.0Hz,1H,Ar-H),7.63(s,1H,Ar-H),7.57(d,J=8.9Hz,1H,Ar-H),7.18–7.12(m,1H,Ar-H),7.06(s,1H,Ar-H),6.9 9(s,1H,Ar-H),6.90(t,J=6.8Hz,1H,Ar-H),4.07(s,1H,OH),3.92(s,3H,Ar-OCH3),3.78(s,3H,Ar-OCH3),2.60(s,3H,COCH3),1.68(s,6H,2×CH3).

[0274] Example 12

[0275] Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)indoleazin-3-yl)acet-1-one

[0276] Step 1: Synthesis of 1-bromo-4-(bromomethyl)-2,5-dimethoxybenzene

[0277] Dissolve (4-bromo-2,5-dimethoxyphenyl)methanol (247.09 mg, 200 mg, 0.81 mmol, 1 eq) in dichloromethane. Slowly add phosphorus tribromide (270.69 mL, 0.11 mL, 1.21 mmol, 1.5 eq) in an ice bath. React at 0 °C for 30 minutes. After the reaction is complete, quench with saturated NaHCO3 solution until no gas is generated. Concentrate under vacuum to remove the solvent. Extract with ethyl acetate / saturated NaCl solution. Back-extract once with dichloromethane. Dry with anhydrous sodium sulfate and then perform column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid product 1-bromo-4-(bromomethyl)-2,5-dimethoxyphenyl (309.99 mg, 205 mg, 0.66 mmol, 82%). 1 H NMR (500MHz, DMSO-d6): δ7.26(s,1H,Ar-H),7.24(s,1H,Ar-H),4.61(s,2H,CH2),3.82(s,3H,OCH3),3.79(s,3H,OCH3).

[0278] Step 2, 1-(4-bromo-2,5-dimethoxybenzyl)-1H imidazole

[0279] 1-Bromo-4-(bromomethyl)-2,5-dimethoxybenzyl (309.99 g, 1.7 g, 5.48 mmol, 1 eq) was dissolved in dichloromethane, and imidazole (68.08 mg, 560 mg, 8.22 mmol, 1.5 eq) was added. The reaction was carried out at room temperature for two small-scale tests. After the reaction was completed, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (pure ethyl acetate) to give 1-(4-bromo-2,5-dimethoxybenzyl)-1H imidazole (297.15 g, 505 mg, 1.7 mmol, 31%). 1 H NMR (400MHz, CDCl3): δ7.55(s,1H,Ar-H),7.08(s,1H,Ar-H),7.05(s,1H,Ar-H),6.91(s ,1H,Ar-H),6.51(s,1H,Ar-H),5.05(s,2H,CH2),3.80(s,3H,OCH3),3.75(s,3H,OCH3).

[0280] Step 3: Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)acet-1-one

[0281] The synthesis method is the same as in Example 1, with a yield of 35%. 1H NMR (500MHz, DMSO-d6): δ9.78(d,J=7.1Hz,1H,Ar-H),7.84(s,1H,Ar-H),7.74(s,1H,Ar-H),7.57(d,J=9.0Hz,1H,Ar-H),7.28–7.23(m,1H,Ar- H),7.22(s,1H,Ar-H),7.08–7.02(m,3H,3×Ar-H),6.90(s,1H,Ar-H),5.17(s,2H,CH2),3.84(s,3H,OCH3),3.68(s,3H,OCH3),2.53(s,3H,CH3).

[0282] Example 13

[0283] Synthesis of 1-(1-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0284] Step 1: Synthesis of 1-(4-bromo-2,5-dimethoxyphenyl)-N,N-dimethylmethylamine

[0285] The synthesis method is the same as in Example 12, with a yield of 86%. 1 H NMR (500MHz, Methanol-d4): δ7.18(s,1H,Ar-H),7.02(s,1H,Ar-H),3.83(s,3H,OCH3),3.79(s,3H,OCH3),3.64(s,2H,CH2),2.36(s,6H,2×NCH3).

[0286] Step 2: Synthesis of 1-(1-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0287] The synthesis method is the same as in Example 1, with a yield of 56%. 1 H NMR (500MHz, CDCl3): δ9.90(d,J=7.1Hz,1H,Ar-H),7.64(s,1H,Ar-H),7.58(d,J=8.9Hz,1H,Ar-H),7.17–7.12(m,1H,Ar-H),7.05(s,1H,Ar-H),6 .94(s,1H,Ar-H),6.90(t,J=6.8Hz,1H,Ar-H),3.83(s,3H,OCH3),3.80(s,3H,OCH3),3.52(s,2H,CH2),2.60(s,3H,COCH3),2.33(s,6H,2×NCH3).

[0288] Example 14

[0289] Synthesis of 1-(1-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)indoleazin-3-yl)ethyl-1-one

[0290] Step 1: Synthesis of 1-(4-bromo-2,6-dimethoxyphenyl)-N,N-dimethylmethylamine

[0291] 4-Bromo-2,6-dimethoxybenzaldehyde (245.07 g, 12.24 mmol, 1 eq) was dissolved in methanol, and dimethylamino alcohol solution (45.08 mL, 36.72 mmol, 3 eq) was added. After reacting overnight at room temperature, the system turned yellow. NaBH4 (37.83 g, 1.4 g, 36.72 mmol, 3 eq) was added under ice bath, and the reaction continued for 1 h until the yellow color disappeared and the system became colorless. The solvent and dimethylamine were removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated NaCl solution, followed by extraction with ethyl acetate / dilute hydrochloric acid. The dilute hydrochloric acid layer was washed twice with dichloromethane, and the pH of the dilute hydrochloric acid layer was adjusted to alkaline with 4M sodium hydroxide solution. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a colorless oily liquid, 1-(4-bromo-2,6-dimethoxyphenyl)-N,N-dimethylmethylamine (274.16 g, 8.39 mmol, 69%). 1 H NMR (500MHz, CDCl3): δ6.69(s,2H,2×Ar-H), 3.79(s,6H,2×OCH3), 3.43(s,2H,CH2), 2.22(s,6H,2×NCH3).

[0292] Step 2: Synthesis of 1-(1-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0293] Dissolve 1-(4-bromo-2,6-dimethoxyphenyl)-N,N-dimethylmethylamine (274.16 mg, 100 mg, 0.36 mmol, 1 eq), 1-(1-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)indolazin-3-yl)ethyl-1-one (271.12 mg, 148 mg, 0.55 mmol, 1.5 eq), Ba(OH)₂·8H₂O (315.46 mg, 460 mg, 1.46 mmol, 4 eq), and PdCl₂(dppf)·CH₂Cl₂ (810.59 mg, 5.91 mg, 0.0073 mmol, 0.02 eq) in a mixed solvent of dioxane / tetrahydrofuran / water = 3:2:1. Under nitrogen protection and evacuation for 10 min, react overnight at 80 °C. After the reaction was completed, the mixture was concentrated under vacuum, extracted with ethyl acetate / saturated brine, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography with petroleum ether:ethyl acetate = 1:1 (1% triethylamine) to give the product (352.43 mg, 0.22 mmol, 61%). 1 H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.84(d,J=8.9Hz,1H,Ar-H),7.61(s,1H,Ar-H),7.23–7.16(m,1H,Ar-H),6.9 2(t,J=6.9Hz,1H,Ar-H),6.73(s,2H,2×Ar-H),3.89(s,6H,2×OCH3),3.55(s,2H,CH2),2.62(s,3H,COCH3),2.30(s,6H,2×NCH3).

[0294] Example 15

[0295] Synthesis of 1-(1-(2,5-dimethoxy-4-(morpholinomethyl)phenyl)-indene-3-yl)ethane-1-one

[0296] The synthesis method is the same as in Example 1, with a yield of 52%. 1H NMR (500MHz, CDCl3): δ9.90 (d, J = 7.0Hz, 1H, Ar-H), 7.64 (s, 1H, Ar-H), 7.58 (d ,J=8.9Hz,1H,Ar-H),7.18–7.12(m,1H,Ar-H),7.11(s,1H,Ar-H),6.94(s,1H,A r-H),6.90(t,J=6.9Hz,1H,Ar-H),3.83(s,3H,OCH3),3.79(s,3H,OCH3),3.78– 3.74(m,4H,2×CH2),3.61(s,2H,CH2),2.60(s,3H,COCH3),2.57(s,4H,2×CH2).

[0297] Example 16

[0298] Synthesis of 1-(1-(4-((ethyl(methyl)amino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0299] Step 1: Synthesis of N-(4-bromo-2,6-dimethoxybenzyl)-N-methylethylamine

[0300] The synthesis method is the same as in Example 13, with a yield of 59%. 1 H NMR (500MHz, DMSO-d6): δ6.82(s,2H,2×Ar-H),3.76(s,6H,2×OCH3),3.38(s,2H,CH2),2.34(m,2H,NCH2CH3),2.02(s,3H,NCH3),0.97(t,J=7Hz,3H,NCH2CH3).

[0301] Step 2: Synthesis of 1-(1-(4-((ethyl(methyl)amino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0302] The synthesis method is the same as in Example 13, with a yield of 59%. 1H NMR (500MHz, CDCl3): δ9.92 (d, J=7.1Hz, 1H, Ar-H), 7.84 (d, J=8.9Hz, 1H, Ar-H), 7.60(s,1H,Ar-H),7.22–7.16(m,1H,Ar-H),6.92(dd,J=9.9,3.9Hz,1H,Ar-H),6. 73(s,2H,2×Ar-H),3.89(s,6H,2×OCH3),3.61(s,2H,CH2),2.62(s,3H,COCH3),2. 56(q,J=7.1Hz,2H,NCH2CH3),2.26(s,3H,NCH3),1.16(t,J=7.1Hz,3H,NCH2CH3).

[0303] Example 17

[0304] Synthesis of 4-(3-acetylindoleazine-1-yl)-2,6-dimethoxy-N,N-dimethylbenzamide

[0305] Step 1: Synthesis of 4-bromo-2,6-dimethoxybenzoic acid

[0306] Using the intermediate from Example 27 as raw material, the hydrolysis method was the same as in Example 1. Yield: 74%. 1 H NMR (500MHz, DMSO-d6): δ12.89(s,1H,COOH),6.92(s,2H,2×Ar-H),3.78(s,6H,2×OCH3).

[0307] Step 2: Synthesis of 4-bromo-2,6-dimethoxy-N,N-dimethylbenzamide

[0308] 4-Bromo-2,6-dimethoxybenzoic acid (261.07 g, 3.83 mmol, 1 eq), HATU (380.24 g, 2.18 g, 5.75 mmol, 1.5 qe), and DIPEA (129.24 mL, 11.49 mmol, 3 eq) were dissolved in DMF and the mixture was allowed to turn yellow. Then, dimethylamine hydrochloride (81.54 mg, 374 mg, 4.59 mmol, 1.2 eq) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was complete, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated brine, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the product 4-bromo-2,6-dimethoxy-N,N-dimethylbenzamide (288.14 g, 500 mg, 1.74 mmol, 45%). 1H NMR (500MHz, CDCl3): δ6.72(s,2H,2×Ar-H), 3.79(s,6H,2×OCH3), 3.10(s,3H,NCH3), 2.81(s,3H,NCH3).

[0309] Step 3: Synthesis of 4-(3-acetylindoleazine-1-yl)-2,6-dimethoxy-N,N-dimethylbenzamide

[0310] The synthesis method is the same as in Example 1, with a yield of 59%. 1 H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.81(d,J=8.9Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.24–7.18(m,1H,Ar-H),6. 93(t,J=6.9Hz,1H,Ar-H),6.73(s,2H,2×Ar-H),3.88(s,6H,2×OCH3),3.16(s,3H,NCH3),2.92(s,3H,NCH3),2.62(s,3H,COCH3).

[0311] Example 18

[0312] Synthesis of 1-(1-(3-(dimethylamino)-4-((dimethylamine)methyl)-5-methoxyphenyl)-indene-3-yl)ethane-1-one

[0313] Step 1: Synthesis of 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde

[0314] 4-Bromo-2,6-difluorobenzaldehyde (221.0 g, 9.05 mmol, 1 eq) was dissolved in 100 mL of DMF, and KOH (56.11 g, 18.1 mmol, 2 eq) was dissolved in 15 mL of H₂O and slowly added dropwise to the reaction solution. The reaction was carried out at 60 °C for 2 h. After the reaction was completed, the mixture was extracted with ethyl acetate / dilute hydrochloric acid, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 50:1) to give 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde (246.08 g, 1.1 g, 4.47 mmol, 49%). 1 H NMR (400MHz, CDCl3): δ10.18(s,1H,CHO),6.91(s,1H,Ar-H),6.77(d,J=10.3Hz,1H,Ar-H),2.93(s,6H,2×NCH3).

[0315] Step 2: Synthesis of 4-bromo-2-(dimethylamino)-6-methoxybenzaldehyde

[0316] Dissolve 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde (246.08 g, 1.1 g, 4.47 mmol, 1 eq) in methanol, add NaOCH3 (54.02 g, 8.12 mmol, 0.75 mL, 2 eq), reflux for 6 h, and after the reaction is complete, extract with ethyl acetate / saturated brine, dry with anhydrous sodium sulfate, and then column chromatography (petroleum ether: ethyl acetate = 30:1) to give 4-bromo-2-(dimethylamino)-6-methoxybenzaldehyde (257.01 g, 0.6 g, 2.33 mmol, 52%). 1 H NMR (500MHz, CDCl3): δ10.25(s,1H,CHO),6.73(s,1H,Ar-H),6.55(d,J=1Hz,1H,Ar-H),3.87(s,3H,OCH3),2.89(s,6H,2×NCH3).

[0317] Step 3: Synthesis of 5-bromo-2-((dimethylamino)methyl)-3-methoxy-N,N-dimethylaniline

[0318] Refer to Example 14. 1 H NMR (500MHz, CDCl3): δ6.86 (s, J=2Hz, 1H, Ar-H), 6.74 (d, J=1.5Hz, 1H, Ar-H), 3 .76(s,3H,OCH3),3.45(s,2H,CH2),2.67(s,6H,2×OCH3),2.20(s,6H,2×NCH3).

[0319] Step 4: Synthesis of 1-(1-(3-(dimethylamino)-4-((dimethylamine)methyl)-5-methoxyphenyl)-indene-3-yl)ethane-1-one

[0320] Refer to Example 1. 1 H NMR (500MHz, DMSO): δ9.81(d,J=7.1Hz,1H,Ar-H),8.03(s,1H,Ar-H),7.99(d,J=9.0Hz,1H,Ar-H),7.38-7.29(m,1H,Ar-H),7.08(t,J=6.5Hz,1H ,Ar-H),6.97(s,1H,Ar-H),6.94(s,1H,Ar-H),3.85(s,3H,OCH3),3.48(s,2H,CH2),2.80(s,6H,2×OCH3),2.58(s,3H,CH3),2.20(s,6H,2×NCH3).

[0321] Example 19

[0322] Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)-indene-3-yl)prop-1-one

[0323] Step 1: Synthesis of 1-(2-O-Butyl)pyridine ammonium chloride

[0324] Referring to Example 1, the yield was 71%. 1 H NMR (500MHz, DMSO-d6): δ8.91 (d, J=6.0Hz, 2H, 2×Ar-H), 8.68 (t, J=7.8Hz, 1H, Ar-H), 8.23 ​​(t, J=6. 9Hz,2H,2×Ar-H),5.87(s,2H,CH2),2.69(q,J=7.2Hz,2H,CH2CH3),1.02(t,J=7.2Hz,3H,CH2CH3).

[0325] Step 2: Synthesis of methyl 3-butyrylindolazine-1-carboxylate

[0326] Referring to Example 1, the yield was 60%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.0Hz,1H,Ar-H),8.26(d,J=8.9Hz,1H,Ar-H),8.14(s,1H,Ar-H),7.62-7.52(m,1 H, Ar-H), 7.23 (t, J = 6.9Hz, 1H, Ar-H), 3.84 (s, 3H, CH3), 2.99 (q, J = 7.3Hz, 2H, CH2CH3), 1.12 (t, J = 7.3Hz, 3H, CH2CH3).

[0327] Step 3: Synthesis of 3-butyrylindoleazine-1-carboxylic acid

[0328] Referring to Example 1, the yield was 90%. 1 H NMR (500MHz, DMSO-d6): δ12.51(s,1H,COOH),9.81(d,J=7.0Hz,1H,Ar-H),8.28(d,J=8.9Hz,1H,Ar-H),8.11(s,1H,Ar- H),7.58-7.47(m,1H,Ar-H),7.21(t,J=6.6Hz,1H,Ar-H),2.99(q,J=7.3Hz,2H,CH2CH3),1.12(t,J=7.4Hz,3H,CH2CH3).

[0329] Step 4: Synthesis of 1-(1-bromoindol-3-yl)prop-1-one

[0330] Referring to Example 1, the yield was 73%. 1 H NMR (500MHz, CDCl3): δ9.86 (d, J=7.1Hz, 1H, Ar-H), 7.61–7.47 (d&s, 2H, 2×Ar-H), 7.25-7.14 (m, 1H , Ar-H), 6.90 (t, J=6.9Hz, 1H, Ar-H), 2.89 (q, J=7.4Hz, 2H, CH2CH3), 1.26 (t, J=7.4Hz, 3H, CH2CH3).

[0331] Step 5: Synthesis of 1-(1-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)indolazin-3-yl)prop-1-one

[0332] Referring to Example 1, the yield was 25%. 1 H NMR (500MHz, CDCl3): δ9.89 (d, J=7.1Hz, 1H, Ar-H), 7.57-7.47 (d&s, 2H, 2×Ar-H), 7.15-7.07 (m, 1H, Ar-H), 6.85 (t, J=6 .9Hz,1H,Ar-H),3.65(s,4H,2×CH2),2.93(q,J=7.5Hz,2H,CH2CH3),1.28(t,J=7.5Hz,3H,CH2CH3),0.98(s,6H,2×CH3).

[0333] Step 6: Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)-indene-3-yl)prop-1-one

[0334] Referring to Example 1, the yield was 53%. 1 H NMR (500MHz, CDCl3): δ9.95 (d, J=7.0Hz, 1H, Ar-H), 7.80 (d, J=8.9Hz, 1H, Ar-H), 7. 67(s,1H,Ar-H),7.61(s,1H,Ar-H),7.23-7.16(m,1H,Ar-H),7.05(s,1H,Ar-H),6.9 9(s,1H,Ar-H),6.92(t,J=6.8Hz,1H,Ar-H),6.73(s,2H,2×Ar-H),5.19(s,2H,CH2), 3.93(s,6H,2×OCH3),2.99(q,J=7.4Hz,2H,CH2CH3),1.30(t,J=7.4Hz,3H,CH2CH3).

[0335] Example 20

[0336] Referring to Example 19, the yield was 43%. 1 H NMR (500MHz, DMSO-d6): δ9.80 (d, J=6.5Hz, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.73 ( s,1H,Ar-H),7.57(d,J=8.9Hz,1H,Ar-H),7.27-7.18(m,2H,2×Ar-H),7.05(d,J =8.4Hz,3H,3×Ar-H),6.89(s,1H,Ar-H),5.16(s,2H,CH2),3.84(s,3H,OCH3),3 .67(s,3H,OCH3),2.95(d,J=7.3Hz,2H,CH2CH3),1.15(t,J=7.1Hz,3H,CH2CH3).

[0337] Example 21

[0338] Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-(benzyloxy)azind-3-yl)ethane-1-one

[0339] Step 1: Synthesis of 1-(2-oxopropyl)-4-(benzyloxy)-pyridine chloride

[0340] Referring to Example 1, the yield was 90%. 1 H NMR (400MHz, DMSO-d6): δ8.70(d,J=7.2Hz,2H,2×Ar-H),7.77(d,J=7.6Hz,2H,2×Ar-H),7.53(d,J=6. 4Hz,2H,2×Ar-H),7.45-7.40(m,3H,3×Ar-H),5.63(s,2H,CH2),5.50(s,2H,OCH2),2.28(s,3H,CH3).

[0341] Step 2: Synthesis of methyl 3-acetyl-7-(benzyloxy)indoleazine-1-carboxylate

[0342] Referring to Example 1, the yield was 68%. 1 H NMR (400MHz, CDCl3): δ9.75 (d, J=7.6Hz, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.78 (d, J=2.4Hz, 1H, Ar-H), 7.51-7.36 (m,5H,5×Ar-H),6.77(dd,J=7.6,2.8Hz,1H,2×Ar-H),5.19(s,2H,OCH2),3.91(s,3H,OCH3),2.54(s,3H,CH3).

[0343] Step 3, 3-acetyl-7-(benzyloxy)indoleazine-1-carboxylic acid

[0344] Referring to Example 1, the yield was 86%. 1 H NMR (400MHz, DMSO-d6): δ12.31(s,1H),9.65(d,J=7.6Hz,1H),8.03(s,1H),7.72(d,J=2.8Hz ,1H),7.52(s,1H),7.53-7.35(m,4H),6.99(dd,J=7.7,2.7Hz,1H),5.26(s,2H),2.50(s,3H).

[0345] Step 4: Synthesis of 1-(7-(benzyloxy)-1-bromoindoleazine-3-yl)ethyl-1-one

[0346] Referring to Example 1, the yield was 40%. 1 H NMR (500MHz, DMSO-d6): δ9.63 (d, J=7.7Hz, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.50 (d, J=7.4Hz, 2H, 2×Ar-H), 7.42 (t, J=7.5Hz, 2H, 2×Ar- H),7.36(t,J=7.2Hz,1H,Ar-H),6.98(d,J=2.2Hz,1H,Ar-H),6.89(dd,J=7.7,2.3Hz,1H,Ar-H),5.27(s,2H,OCH2),2.44(s,3H,CH3).

[0347] Step 5: Synthesis of 1-(7-(benzyloxy)-1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one

[0348] Referring to Example 1, the yield was 58%. 1H NMR (500MHz, DMSO-d6): δ9.70 (d, J=7.7Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.45 (d, J=7.4Hz, 2H, 2×Ar-H),7.40(t,J=7.5Hz,2H,2×Ar-H),7.34(t,J=7.1Hz,1H,Ar-H),7.17(s,1H,Ar-H),6.94– 6.90(m,2H,2×Ar-H),6.86(dd,J=7.7,2.5Hz,1H,Ar-H),5.18(s,2H,CH2Ph),5.10(t,J=5.5Hz, 1H,OH),4.55(d,J=5.4Hz,2H,CH2OH),3.75(s,3H,OCH3),3.67(s,3H,OCH3),2.48(s,3H,CH3).

[0349] Step 6: Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-(benzyloxy)azind-3-yl)ethane-1-one

[0350] Dissolve 1-(7-(benzyloxy)-1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)indolazin-3-yl)ethane-1-one (431.17 mg, 200 mg, 0.464 mmol, 1 eq) in dichloromethane, slowly add 200 μL of PBr3, then add imidazole (68.08 mg, 252 mg, 3.71 mmol, 8 eq), and react overnight at room temperature. After the reaction is complete, concentrate under vacuum to remove the solvent, extract with ethyl acetate / saturated NaCl solution, back-extract once with dichloromethane, dry with anhydrous sodium sulfate, and then perform column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 61 mg of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-(benzyloxy)indolazin-3-yl)ethane-1-one. 1 H NMR (500MHz, CDCl3): δ9.81(d,J=8.0Hz,1H),7.54(s,1H),7.41–7.34(m,6H),6.91(s,1H),6.83(d,J=2.5 Hz,1H),6.71–6.69(m,1H),6.66(s,1H),5.16(s,2H),5.07(s,2H),3.80(s,3H),3.63(s,3H),2.54(s,3H).

[0351] Example 22

[0352] Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-hydroxyazind-3-yl)ethane-1-one

[0353] The double-necked flask was dried, and Pd(OAc)2 (224.51 mg, 11.7 mg, 0.05 mmol, 0.5 eq) and NaH (24 mg, 3.6 mg, 0.15 mmol, 1.5 eq) were added. After evacuating the air for 5 minutes, ultra-dry DMF solution was injected and stirred until the system turned black. 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-(benzyloxy)azind-3-yl)ethane-1-one (481.2 mg, 50 mg, 0.1 mmol, 1 eq) was dissolved in DMF and slowly injected. The reaction was carried out at 50 °C for 3 h. After the reaction was complete, the solvent was removed by vacuum concentration, extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (ethyl acetate:methanol = 10:1) to give 14.9 mg of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-hydroxy-indene-3-yl)ethane-1-one. 1 H NMR (500MHz, DMSO-d6): δ10.47(s,1H),9.67(d,J=7.6Hz,1H),8.18(s,1H),7.72(s,1H),7.38(s,1H),7.13(s,1H),7.09(s ,1H),7.03(s,1H),6.78(d,J=2.5Hz,1H),6.70(dd,J=7.6,2.5Hz,1H),5.23(s,2H),3.83(s,3H),3.70(s,3H),2.44(s,3H).

[0354] Example 23

[0355] Synthesis of 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-inden-7-yl dimethylcarbamate

[0356] Dissolve 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-hydroxy-indane-3-yl)ethane-1-one (391.15, 40 mg, 0.1 mmol, 1 eq) and NaOH (40, 4.9 mg, 0.123 mmol, 1.2 eq) in acetonitrile, add dimethylcarbamoyl chloride (107.54, 11.3 μL, 0.123 mmol, 1.2 eq), and reflux overnight. After the reaction was complete, the solvent was removed by vacuum concentration, extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried with anhydrous sodium sulfate, and then subjected to column chromatography (dichloromethane:methanol = 100:1) to give 22 mg of 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-indene-7-yl dimethylcarbamate. 1 H NMR (500MHz, CDCl3): δ9.85(d,J=7.7Hz,1H),7.64(s,1H),7.59(s,1H),7.30(d,J=2.3Hz,1H),7.07(s,1H),7.01(s,1H),6.94( s,1H),6.74(dd,J=7.6,2.4Hz,1H),6.65(s,1H),5.14(s,2H),3.84(s,3H),3.68(s,3H),3.07(s,3H),2.99(s,3H),2.55(s,3H).

[0357] Example 24

[0358] 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-indene-7-ylmethanesulfonate

[0359] Referring to Example 23, the yield was 6%. 1 H NMR (500MHz, CDCl3): δ9.93(d,J=7.7Hz,1H),7.65(s,2H),7.48(d,J=2.1Hz,1H),7.10(s,1H),7.02(s,1H),6 .94(s,1H),6.85–6.81(m,1H),6.66(s,1H),5.17(s,2H),3.87(s,3H),3.71(s,3H),3.20(s,3H),2.60(s,3H).

[0360] Example 25

[0361] Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxy-indene-3-yl)ethane-1-one

[0362] Step 1: Synthesis of 4-methoxy-1-(2-oxopropyl)-pyridine chloride

[0363] Referring to Example 1, the yield was 84%. 1 H NMR (400MHz, DMSO-d6): δ8.71(d,J=6.8Hz,2H,2×Ar-H), 8.69(d,J=7.2Hz,2H,2×Ar-H), 5.66(s,2H,CH2), 4.11(s,3H,OCH3), 2.28(s,3H,CH3).

[0364] Step 2: Synthesis of methyl 3-acetyl-7-methoxyindoleazine-1-carboxylate

[0365] Referring to Example 1, the yield was 43%. 1 H NMR (400MHz, CDCl3): δ9.72(d,J=7.6Hz,1H,Ar-H),7.89(s,1H,Ar-H),7.76(d,J=2.4Hz,1H,Ar -H),6.69(dd,J=8.0,2.8Hz,1H,Ar-H),3.94(s,3H,OCH3),3.91(s,3H,OCH3),2.53(s,3H,CH3).

[0366] Step 3: Synthesis of 3-acetyl-7-methoxyindoleazine-1-carboxylic acid

[0367] Referring to Example 1, the yield was 87%. 1 H NMR (500MHz, DMSO-d6): δ12.45(s,1H,COOH),9.64(d,J=7.8Hz,1H,Ar-H),8.03(s,1H,Ar -H),7.61(s,1H,Ar-H),6.92(d,J=7.7Hz,1H,Ar-H),3.91(s,3H,OCH3),2.50(s,3H,CH3).

[0368] Step 4: Synthesis of 1-(1-bromo-7-methoxyindolin-3-yl)ethane-1-one

[0369] Referring to Example 1, the yield was 41%. 1 H NMR (500MHz, DMSO-d6): δ9.61 (d, J=7.6Hz, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 6.85 (s, 1H, Ar-H), 6.83 (dd, J=7.6, 2.5Hz, 1H, Ar-H), 3.91 (s, 3H, OCH3), 2.44 (s, 3H, CH3).

[0370] Step 5: Synthesis of 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-7-methoxy-indene-3-yl)ethane-1-one

[0371] Referring to Example 1, the yield was 47%. 1 H NMR (500MHz, DMSO-d6): δ9.67(d,J=7.7Hz,1H,Ar-H),7.76(s,1H,Ar-H),7.19(s,1H,Ar-H),6.98(s,1H,Ar-H),6.82(d,J=2.3Hz,1H,Ar-H),6.78(dd,J=7 .7,2.6Hz,1H,Ar-H),5.12(t,J=5.5Hz,1H,OH),4.55(d,J=5.4Hz,2H,CH2),3 .82(s,3H,OCH3),3.79(s,3H,OCH3),3.76(s,3H,OCH3),2.48(s,3H,COCH3).

[0372] Step 6: Synthesis of 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxy-indene-3-yl)ethane-1-one

[0373] Referring to Example 21, the yield was 46%. 1 H NMR (500MHz, CDCl3): δ9.77(d,J=7.7Hz,1H),7.63(s,1H),7.54(s,1H),7.08(s,1H),7.03(s,1H),6.96(s,1H),6.76(d,J =2.6Hz,1H),6.69(s,1H),6.61(dd,J=7.7,2.6Hz,1H),5.16(s,2H),3.85(s,3H),3.81(s,3H),3.71(s,3H),2.53(s,3H).

[0374] Example 26

[0375] Synthesis of 1-(1-(4-((1H-pyrazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxy-indene-3-yl)ethane-1-one

[0376] Referring to Example 25, the yield was 61%. 1H NMR (500MHz, CDCl3): δ9.79(d,J=7.5Hz,1H),7.64(s,1H),7.54(s,1H),7.09(s,1H),7.03(s,1H),6.97(s,1H),6.76(d,J =2.5Hz,1H),6.68(s,1H),6.62(dd,J=7.5,2.5Hz,1H),5.16(s,2H),3.86(s,3H),3.82(s,3H),3.71(s,3H),2.54(s,3H).

[0377] Example 27

[0378] Synthesis of 1-(1-(2,5-dimethoxy-4-((2-thio-1,3,4-thiadiazol-3(2H)-yl)methyl)phenyl)-7-methoxy-indene-3-yl)ethane-1-one

[0379] Referring to Example 25, the yield was 29%. 1 H NMR (500MHz, CDCl3): δ9.78(d,J=7.7Hz,1H),9.02(s,1H),7.55(s,1H),7.18(s,1H),6.96(s,1H),6.79(d,J =2.6Hz,1H),6.61(dd,J=7.7,2.6Hz,1H),4.71(s,2H),3.88(s,3H),3.82(s,3H),3.78(s,3H),2.54(s,1H).

[0380] Example 28

[0381] Synthesis of 3-(3-acetylindololin-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide

[0382] Step 1: Synthesis of 3-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid

[0383] Referring to Example 1, the yield was 45%. 1 H NMR (500MHz, DMSO-d6): δ9.78(d,J=6.0Hz,1H),7.96(s,2H),7.86(s,1H),7.52(d,J=8.3Hz,1H),7.32–7.19(m,2H),7.07(s,1H),2.50(s,3H).

[0384] Step 2: Synthesis of 3-(3-acetylindoline-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide

[0385] 3-(3-acetyl-indoline-1-yl)-4-methoxybenzoic acid (309.32 mg, 50 mg, 0.162 mmol, 1 eq), benzenesulfonamide (157.19 mg, 25.5 mg, 0.162 mmol, 1 eq), EDCI·HCl (191.70 mg, 52.3 mg, 0.323 mmol, 2 eq), and DMAP (122.17 mg, 39.5 mg, 0.323 mmol, 2 eq) were dissolved in DCM and reacted overnight at room temperature. After the reaction was complete, the solution was concentrated under vacuum, extracted with ethyl acetate / saturated NaCl solution, back-extracted with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 4:1, 1% TFA) to give 19 mg of 3-(3-acetylindoline-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide. 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),9.79(d,J=6.5Hz,1H),8.01(d,J=7.5Hz,2H),7.97(s,1H),9.94(d,J=8.5Hz,1H),7.86(s, 1H),7.73–7.71(m,1H),7.69–7.63(m,2H),7.53(d,J=8.5Hz,1H),7.30–7.24(m,2H),7.08–7.06(m,1H),3.85(s,3H),2.54(s,3H).

[0386] Example 29

[0387] 3-(3-acetylindololin-1-yl)-4-methoxy-N-(methylsulfonyl)benzamide

[0388] Referring to Example 28, the yield was 71%. 1 H NMR (500MHz, CDCl3): δ9.82(d,J=7.1Hz,1H),9.25(s,1H),7.99(s,1H),7.91(d,J=8.6Hz,1H),7.59(s,1H),7.48(d,J =8.8Hz,1H),7.19–7.13(m,1H),7.10(d,J=8.6Hz,1H),6.87(t,J=6.7Hz,1H),3.92(s,3H),3.45(s,3H),2.56(s,3H).

[0389] Example 30

[0390] Synthesis of 3-(3-acetylindolysin-1-yl)-N-cyclopropyl-5-methoxybenzamide

[0391] Step 1: Synthesis of 3-bromo-N-cyclopropyl-5-methoxybenzamide

[0392] 3-Bromo-5-methoxybenzoic acid (231.04 mg, 500 mg, 2.16 mmol, 1 eq) was dissolved in 50 mL of dichloromethane, and thionyl chloride (118.97 mg, 1.82 mL, 21.64 mmol, 10 eq) was slowly added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent and thionyl chloride were removed by vacuum concentration. The system was then dissolved in dichloromethane, and cyclopropylamine (57.09 mg, 0.6 mL, 8.66 mmol, 4 eq) was slowly added dropwise under ice bath conditions. The reaction was allowed to proceed for 5 hours at room temperature. After the reaction was complete, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 3:1) to give 3-bromo-N-cyclopropyl-5-methoxybenzoamide (270.13 mg, 410 mg, 1.52 mmol, 70%). 1 H NMR (500MHz, DMSO-d6): δ8.52(d,J=3.6Hz,1H,CONH),7.56(s,1H,Ar-H),7.38–7.33(m,1H,Ar-H),7.32–7. 26(m,1H,Ar-H),3.81(s,3H,OCH3),2.86–2.78(m,1H,CH),0.73–0.65(m,2H,CH2),0.61–0.53(m,2H,CH2).

[0393] Example 31

[0394] Synthesis of N-(3-(3-acetylindololin-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0395] Step 1: Synthesis of 1-(1-(5-amino-2-methoxyphenyl)-indene-3-yl)ethyl-1-one

[0396] Referring to Example 1, the yield was 51%. 1 H NMR (500MHz, DMSO-d6): δ9.77(d,J=6.9Hz,1H),7.74(s,1H),7.55(d,J=9.0Hz,1H),7.25(t,J=7.7Hz,1H), 7.04(t,J=6.9Hz,1H),6.86(d,J=8.7Hz,1H),6.68(s,1H),6.57(d,J=8.6Hz,1H),3.61(s,3H),2.52(s,3H).

[0397] Step 2: Synthesis of N-(3-(3-acetylindololin-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0398] Referring to Example 23, the yield was 40%.1 H NMR (500MHz, DMSO-d6): δ9.98(s,1H),9.75(d,J=6.9Hz,1H),7.74(d,J=7.7Hz,2H),7.70–7.64(m ,2H),7.59(t,J=7.4Hz,2H),7.24(q,J=8.9Hz,2H),7.09–7.00(m,4H),3.71(s,3H),2.51(s,3H).

[0399] Example 32

[0400] Synthesis of 3-(3-acetyl-inden-1-yl)-N-((4-acetylphenyl)sulfonyl)-4-methoxybenzamide

[0401] Referring to Example 28, the yield was 38%. 1 H NMR (500MHz, CDCl3): δ9.77(d,J=7.1Hz,1H),8.25(d,J=8.4Hz,2H),8.08(d,J=8.4Hz,2H),7.96(d,J=2.2Hz,1H),7.87(dd,J=8.8,2.2Hz,1H) ,7.52(s,1H),7.43(d,J=8.9Hz,1H),7.18–7.09(m,1H),7.05(d,J=8.7Hz,1H),6.82(t,J=6.8Hz,1H),3.89(s,3H),2.65(s,3H),2.53(s,3H).

[0402] Example 33

[0403] Synthesis of 3-(3-acetyl-inden-1-yl)-4-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide

[0404] Referring to Example 28, the yield was 41%. 1 H NMR (500MHz, DMSO-d6): δ12.28(s,1H),9.79(d,J=6.9Hz,1H),7.94(dd,J=16.6,7.6Hz,4H),7.86(s,1H),7.53(d,J=8.8H z,1H),7.31–7.26(m,1H),7.24(d,J=8.7Hz,1H),7.15(d,J=8.7Hz,2H),7.08(t,J=6.5Hz,1H),3.85(s,6H),2.54(s,3H).

[0405] Example 34

[0406] Synthesis of methyl 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoate

[0407] Step 1: Synthesis of methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate

[0408] Methyl 5-bromo-4-methoxy-2-methylbenzoate (259.10 g, 1.0 g, 3.86 mmol, 1 eq) was dissolved in carbon tetrachloride and heated to 90 °C. AIBN (164.21 mg, 63.38 mg, 0.386 mmol, 0.1 eq) and NBS (177.98 mg, 755.6 mg, 4.25 mmol, 1.1 eq) were added successively, and the reaction was allowed to proceed for 4 hours. After the reaction was complete, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated Na₂S₂O₃ solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 80:1) to obtain 521 mg of 3-(3-acetyl-inden-1-yl)-4-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide. 1 H NMR (500MHz, CDCl3): δ8.22(s,1H),7.26(s,1H),6.94(s,1H),4.96(s,2H),3.98(s,3H),3.91(s,3H).

[0409] Step 2: Synthesis of methyl 2-((1H-imidazol-1-yl)methyl)-5-bromo-4-methoxybenzoate

[0410] Methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate (335.90 mg, 200 mg, 0.60 mmol, 1 eq) and excess imidazole were dissolved in a DCM / MeOH mixed solvent and reacted at 60 °C for 3 hours. After the reaction was completed, the solvent was removed by vacuum concentration, extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (dichloromethane:methanol = 10:1) to give 189 mg of methyl 2-((1H-imidazol-1-yl)methyl)-5-bromo-4-methoxybenzoate. 1 H NMR (500MHz, CDCl3): δ8.26(s,1H),7.59(s,1H),7.13(s,1H),6.95(s,1H),6.19(s,1H),5.58(s,2H),3.89(s,3H),3.75(s,3H).

[0411] Step 3: Synthesis of methyl 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoate

[0412] Referring to Example 1, the yield was 59%. 1 H NMR (500MHz, CDCl3): δ9.90(d,J=7.1Hz,1H),8.15(s,1H),7.68(s,1H),7.63(s,1H),7.49(d,J=8.9Hz,1H),7.26(s,2H), 7.20–7.14(m,2H),7.03(s,1H),6.92(t,J=6.9Hz,1H),6.38(s,1H),5.67(s,2H),3.90(s,3H),3.72(s,3H),2.59(s,3H).

[0413] Example 35

[0414] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide

[0415] Referring to Example 28, the yield was 5%. 1 H NMR (500MHz, CD3OD_SPE): δ9.85(brs,1H),8.83(s,1H),8.05(brs,2H),7.85(d,J=7.0Hz,2H),7.69(s,1H),7. 60(brs,3H),7.48(s,H),7.42(s,1H),7.34–7.29(m,2H),7.03(s,1H),5.60(s,2H),3.93(s,3H),2.59(s,3H).

[0416] Example 36

[0417] Synthesis of methyl 5-(3-acetyl-inden-1-yl)-2-((dimethylamino)methyl)-4-methoxybenzoate

[0418] Referring to Example 34, the yield was 46%. 1 H NMR (500MHz, CDCl3): δ9.90(d,J=7.1Hz,1H),7.98(s,1H),7.65(s,1H),7.54(d,J=8.9Hz,1H),7.28( s,1H),7.19–7.13(m,1H),6.90(t,J=6.7Hz,1H),3.92(s,3H),3.87(s,5H),2.60(s,3H),2.33(s,6H).

[0419] Example 37

[0420] Synthesis of 3-(3-acetyl-inden-1-yl)-N-cyclopropyl-4-methoxybenzamide

[0421] Referring to Example 30, the yield was 68%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.1Hz,1H),8.33(d,J=3.8Hz,1H),7.89( d,J=1.9Hz,1H),7.88–7.85(m,1H),7.84(s,1H),7.51(d,J=9.0Hz,1H),7.31 –7.25(m,1H),7.20(d,J=8.6Hz,1H),7.07(t,J=6.8Hz,1H),3.83(s,3H),2.8 4(tq,J=7.7,3.9Hz,1H),2.55(s,3H),0.74–0.65(m,2H),0.61–0.51(m,2H).

[0422] Example 38

[0423] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid

[0424] Obtained by hydrolysis in Example 34, referring to step 3 of Example 1. Yield: 52%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.1Hz,1H),9.09(s,1H),8.08(s,1H),7.88(s,1H),7.75(s,1H),7.67(s,1H),7 .55(d,J=8.9Hz,1H),7.35–7.28(m,1H),7.27(s,1H),7.10(t,J=6.8Hz,1H),5.79(s,2H),3.87(s,3H),2.55(s,3H).

[0425] Example 39

[0426] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-((3,5-dichlorophenyl)sulfonyl)-4-methoxybenzamide

[0427] Referring to Example 35, the yield was 41%. 1H NMR (500MHz, DMSO-d6): δ9.77(d,J=7.0Hz,1H),7.92(s,1H),7.81–7.74(m,4H),7.70(s,1H),7.46(d,J=8.9Hz,1H), 7.28–7.21(m,1H),7.16(s,1H),7.05(t,J=6.9Hz,1H),6.83(d,J=5.4Hz,2H),5.63(s,2H),3.70(s,3H),2.53(s,3H).

[0428] Example 40

[0429] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-benzyl-4-methoxybenzamide

[0430] It was obtained by condensation of benzylamine in Example 38, with a yield of 53%, referring to Example 17. 1 H NMR (500MHz, CDCl3): δ9.88 (d, J = 7.1Hz, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.5 2(s,1H),7.43(d,J=8.9Hz,1H),7.34(dd,J=9.8,4.9Hz,2H),7.30(d,J=7.2 Hz,3H),7.18–7.12(m,1H),7.10(s,1H),7.02(s,1H),6.90(t,J=6.4Hz,1H) ,6.63(s,1H),5.53(s,2H),4.58(d,J=5.6Hz,2H),3.76(s,3H),2.56(s,3H).

[0431] Example 41

[0432] Synthesis of 2-((1H-imidazol-1-yl)methyl)-N-benzyl-5-(3-isobutyrylindolazin-1-yl)-4-methoxybenzamide

[0433] Referring to Example 30, the yield was 21%. 1H NMR (500MHz, DMSO) δ9.85(d,J=7.1Hz,1H),8.94(t,J=5.9Hz,1H),7.92(s,1H),7.74(s,1H),7.65–7.63(m,2H),7.34–7.23(m,6H),7. 20(s,1H),7.12–7.03(m,2H),6.88(s,1H),5.46(s,2H),4.48(d,J=5.9Hz,2H),3.78(s,3H),3.58–3.40(m,1H),1.17(d,J=6.8Hz,6H).

[0434] Example 42

[0435] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(methylsulfonyl)benzamide

[0436] Referring to Example 35, the yield was 15%. 1 H NMR (500MHz, CD3OD_SPE): δ9.87(d,J=7.1Hz,1H),9.07(s,1H),8.22(s,1H),7.84(s,1H),7.73(s,1H),7.59(m, 2H),7.42(s,1H),7.35–7.24(m,1H),7.05(t,J=6.9Hz,1H),5.87(s,2H),4.00(s,3H),3.90(s,3H),2.60(s,3H).

[0437] Example 43

[0438] Synthesis of N-(3-(3-acetyl-inden-1-yl)-5-methoxybenzyl)benzenesulfonamide

[0439] Step 1: Synthesis of 1-(1-(3-(aminomethyl)-5-methoxyphenyl)-indene-3-yl)ethyl-1-one

[0440] It was obtained by coupling 1-(1-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)indolazin-3-yl)ethyl-1-one with (3-bromo-5-methoxyphenyl)methylamine Suzuki, with the specific synthesis described in Example 1, yield 45%. 1H NMR (500MHz, CDCl3): δ9.91(d,J=7.1Hz,1H),7.85(d,J=8.9Hz,1H),7.62(s,1H),7.22–7.17(m,1H), 7.13(s,1H),7.01(s,1H),6.91(t,J=7.0Hz,1H),6.85(s,1H),3.93(s,2H),3.88(s,3H),2.61(s,3H).

[0441] Step 2: Synthesis of N-(3-(3-acetyl-inden-1-yl)-5-methoxybenzyl)benzenesulfonamide

[0442] Dissolve 1-(1-(3-(aminomethyl)-5-methoxyphenyl)indene-3-yl)ethyl-1-one (294.14 mg, 200 mmol, 1 eq) in pyridine, add benzenesulfonyl chloride (176.62 mg, 144 mg, 0.82 mmol, 1.2 eq), and react at room temperature for 5 h. After the reaction is complete, extract with dilute hydrochloric acid / ethyl acetate, dry with anhydrous sodium sulfate, and then perform column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 59 mg of N-(3-(3-acetylindene-1-yl)-5-methoxybenzyl)benzenesulfonamide. 1 H NMR (500MHz, DMSO): δ9.80(d,J=7.0Hz,1H),8.24(t,J=6.1Hz,1H),8.00–7.89(m,2H),7.82(d,J=7.3Hz,2H),7.57(m ,3H),7.35(t,J=7.7Hz,1H),7.10(m,2H),7.04(s,1H),6.74(s,1H),4.07(d,J=6.1Hz,2H),3.78(s,3H),2.57(s,3H).

[0443] Example 44

[0444] Synthesis of 2-((1H-imidazol-1-yl)methyl)-N-benzyl-5-(3-(cyclopropanecarbonyl)-inden-1-yl)-4-methoxybenzamide

[0445] Referring to Example 41, the yield was 18%. 1H NMR (500MHz, DMSO) δ9.82(d,J=7.1Hz,1H),8.95(t,J=5.9Hz,1H),8.09(s,1H),7.81(s,1H),7.68(s,1H),7.65(d,J=9.0Hz,1H),7.36–7.30(m,5 H),7.28–7.22(m,3H),7.10(s,1H),7.05(m,1H),5.49(s,2H),4.49(d,J =5.9Hz,2H),3.79(s,3H),2.82–2.74(m,1H),1.04(m,2H),0.94(m,2H).

[0446] Example 45

[0447] Synthesis of 1-(1-(2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0448] The synthesis method is the same as in Example 1, with a yield of 55%. 1 H NMR (400MHz, CDCl3): δ9.90(d,J=4.4Hz,1H),7.65(s,1H),7.59(d,J=7.7Hz,1H),7 .14(s,1H),7.04–6.94(m,2H),6.89(s,2H),3.83(s,3H),3.78(s,3H),2.59(s,3H).

[0449] Example 46

[0450] Synthesis of 1-(1-(3,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0451] The synthesis method is the same as in Example 1, with a yield of 55%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.1Hz,1H),8.02(s,1H),7.97(d,J=9.0Hz,1H),7.35–7.2 9(m,1H),7.07(t,J=6.8Hz,1H),6.78(d,J=2.1Hz,2H),6.46(s,1H),3.82(s,6H),2.56(s,3H).

[0452] Example 47

[0453] Synthesis of 4-(3-acetyl-inden-1-yl)-2,5-dimethoxybenzaldehyde

[0454] The synthesis method is the same as in Example 1, with a yield of 49%. 1H NMR (500MHz, DMSO-d6): δ10.37(s,1H),9.80(d,J=7.0Hz,1H),7.98(s,1H),7.68(d,J=8.9Hz,1H ),7.37–7.31(m,2H),7.29(s,1H),7.11(t,J=6.8Hz,1H),3.96(s,3H),3.79(s,3H),2.57(s,3H).

[0455] Example 48

[0456] Synthesis of 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0457] Step 1: Synthesis of (4-bromo-2,5-dimethoxyphenyl)methanol

[0458] Dissolve 4-bromo-2,5-dimethoxybenzaldehyde (245.07 mg, 500 mg, 2.04 mmol, 1 eq) in methanol, add NaBH4 (37.83 mg, 154 mg, 4.08 mmol, 2 eq), and react at room temperature for 10 minutes. After the reaction is complete, concentrate under vacuum to remove the solvent, extract with ethyl acetate / saturated NaCl solution, back-extract once with dichloromethane, dry with anhydrous sodium sulfate, and then perform column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid product (4-bromo-2,5-dimethoxyphenyl)methanol (247.09 mg, 490 mg, 1.98 mmol, 97%).

[0459] 1H NMR (400MHz, CDCl3): 7.06 (s, 1H, Ar-H), 6.23 (s, 1H, Ar-H), 4.64 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 2.19 (brs, 1H, OH).

[0460] Step 2: Synthesis of 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0461] The synthesis method is the same as in Example 1, with a yield of 68%. 1H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.65(s,1H,Ar-H),7.57(d,J=8.9Hz,1H,Ar-H),7.23–7.12(m,1H,Ar-H),7.06(s,1H,Ar-H),6.98( s,1H,Ar-H),6.94–6.83(m,1H,Ar-H),4.78(d,J=5.6Hz,2H,CH2),3.89(s,3 H,OCH3),3.81(s,3H,OCH3),2.62(s,3H,COCH3),2.46(t,J=6.0Hz,1H,OH).

[0462] Example 49

[0463] Synthesis of 1-(1-(4-(1-hydroxyethyl)-2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0464] Step 1: Synthesis of 1-(4-bromo-2,5-dimethoxyphenyl)ethyl-1-one

[0465] 2,5-Dimethoxybromobenzene (217.06 g, 9.21 mmol, 1 eq) and AlCl3 (133.34 g, 1.84 g, 13.82 mmol, 1.5 eq) were added to the solvent nitrobenzene under nitrogen protection, followed by the slow addition of acetyl chloride (78.5 mL, 1.07 mL, 13.82 mmol, 1.5 eq). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with ice water, extracted with dichloromethane / dilute hydrochloric acid, dried over anhydrous sodium sulfate, and then subjected to column chromatography. The solvent was first removed with pure petroleum ether, and then the product 1-(4-bromo-2,5-dimethoxyphenyl)ethyl-1-one (259.10 g, 210 mg, 0.81 mmol, 9%) was obtained by petroleum ether:ethyl acetate ratio of 10:1. 1 H NMR (400MHz, DMSO-d6): δ7.45(s,1H,Ar-H),7.25(s,1H,Ar-H),3.87(s,3H,OCH3),3.82(s,3H,OCH3),2.53(s,3H,CH3).

[0466] Step 2: Synthesis of 2-(4-bromo-2,5-dimethoxyphenyl)prop-2-ol

[0467] Dissolve 1-(4-bromo-2,5-dimethoxyphenyl)ethyl-1-one (259.10, 100 mg, 0.38 mmol, 1 eq) in tetrahydrofuran. Under nitrogen protection, slowly add methyl magnesium bromide (119.24, 0.02 mL, 0.58 mmol, 1.5 eq) in an ice bath, and slowly raise the temperature to room temperature for 6 hours. After the reaction is complete, quench with NH4Cl, concentrate under vacuum to remove the solvent, extract with ethyl acetate / saturated NaCl solution, and back-extract once with dichloromethane to give the crude product 2-(4-bromo-2,5-dimethoxyphenyl)prop-2-ol (275.14, 68 mg, 0.25 mmol, 64%). 1 H NMR (500MHz, DMSO-d6): δ7.35(s,1H,Ar-H),7.14(s,1H,Ar-H),5.15(s,1H,OH),3.77(s,1H,OCH3),3.75(s,1H,OCH3),1.45(s,6H,2×CH3).

[0468] Step 3: Synthesis of 1-(1-(4-(1-hydroxyethyl)-2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0469] The synthesis method is the same as in Example 1, with a yield of 59%. 1 H NMR (500MHz, CDCl3): δ9.90(d,J=7.0Hz,1H,Ar-H),7.63(s,1H,Ar-H),7.57(d,J=8.9Hz,1H,Ar-H),7.18–7.12(m,1H,Ar-H),7.06(s,1H,Ar-H),6.9 9(s,1H,Ar-H),6.90(t,J=6.8Hz,1H,Ar-H),4.07(s,1H,OH),3.92(s,3H,Ar-OCH3),3.78(s,3H,Ar-OCH3),2.60(s,3H,COCH3),1.68(s,6H,2×CH3).

[0470] Example 50

[0471] Synthesis of 1-(1-(4-(hydroxymethyl)-3,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0472] The synthesis method is the same as in Example 1, with a yield of 49%. 1H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.82(d,J=8.9Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.24–7.16(m,1H,Ar-H),6.93(t,J= 6.8Hz,1H,Ar-H),6.74(s,2H,2×Ar-H),4.84(d,J=6.5Hz,2H,CH2),3.92(s,6H,2×OCH3),2.62(s,3H,COCH3),2.48(t,J=6.6Hz,1H,OH).

[0473] Example 51

[0474] Synthesis of 4-(3-acetyl-7-methoxyindene-1-yl)-2,5-dimethoxybenzaldehyde

[0475] The synthesis method is the same as in Example 1, with a yield of 49%. 1 H NMR (500MHz, CDCl3): δ10.47(s,1H,CHO),9.79(d,J=7.6Hz,1H,Ar-H),7.64(s,1H,Ar-H),7.47(s,1H,Ar-H),7.09(s,1H,Ar -H),6.84(s,1H,Ar-H),6.67–6.61(m,1H,Ar-H),3.95(s,3H,OCH3),3.87(s,3H,OCH3),3.84(s,3H,OCH3),2.56(s,3H,CH3).

[0476] Example 52

[0477] Synthesis of 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-7-methoxy-indene-3-yl)ethyl-1-one

[0478] The synthesis method is the same as in Example 17, with a yield of 49%. 1H NMR (500MHz, DMSO-d6): δ9.67(d,J=7.7Hz,1H,Ar-H),7.76(s,1H,Ar-H),7.19(s,1H,Ar-H),6.98(s,1H,Ar-H),6.82(d,J=2.3Hz,1H,Ar-H),6.78(dd,J=7 .7,2.6Hz,1H,Ar-H),5.12(t,J=5.5Hz,1H,OH),4.55(d,J=5.4Hz,2H,CH2),3 .82(s,3H,OCH3),3.79(s,3H,OCH3),3.76(s,3H,OCH3),2.48(s,3H,COCH3).

[0479] Example 53

[0480] Synthesis of 1-(1-(4-acetyl-2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0481] Step 1: Synthesis of 1-(4-bromo-2,5-dimethoxyphenyl)ethyl-1-one

[0482] 2,5-Dimethoxybromobenzene (217.06 g, 9.21 mmol, 1 eq) and AlCl3 (133.34 g, 1.84 g, 13.82 mmol, 1.5 eq) were added to the solvent nitrobenzene under nitrogen protection, followed by the slow addition of acetyl chloride (78.5 mL, 1.07 mL, 13.82 mmol, 1.5 eq). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with ice water, extracted with dichloromethane / dilute hydrochloric acid, dried over anhydrous sodium sulfate, and then subjected to column chromatography. The solvent was first removed with pure petroleum ether, and then the product 1-(4-bromo-2,5-dimethoxyphenyl)ethyl-1-one (259.10 g, 210 mg, 0.81 mmol, 9%) was obtained by petroleum ether:ethyl acetate ratio of 10:1. 1 H NMR (400MHz, DMSO-d6): δ7.45(s,1H,Ar-H),7.25(s,1H,Ar-H),3.87(s,3H,OCH3),3.82(s,3H,OCH3),2.53(s,3H,CH3).

[0483] Step 2: Synthesis of 1-(1-(4-acetyl-2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one

[0484] The synthesis method is the same as in Example 1, with a yield of 59%. 1H NMR (500MHz, CDCl3): δ9.92(d,J=7.0Hz,1H,Ar-H),7.69(s,1H,Ar-H),7.59(d,J=8.9Hz,1H,Ar-H),7.49(s,1H,Ar-H),7.22–7.17(m,1H,Ar- H),7.07(s,1H,Ar-H),6.93(t,J=6.8Hz,1H,Ar-H),3.94(s,3H,Ar-OCH3),3.84(s,3H,Ar-OCH3),2.69(s,3H,Ar-COCH3),2.61(s,3H,COCH3).

[0485] Example 54

[0486] Synthesis of methyl 4-(3-acetyl-inden-1-yl)-2,6-dimethoxybenzoate

[0487] The synthesis method is the same as in Example 1, with a yield of 59%. 1 H NMR (400MHz, CDCl3): δ9.92(d,J=7.1Hz,1H,Ar-H),7.79(d,J=9.0Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.25–7.19(m,1H, Ar-H), 6.93 (t, J = 6.8Hz, 1H, Ar-H), 6.73 (s, 2H, 2×Ar-H), 3.94 (s, 3H, COOCH3), 3.89 (s, 6H, 2×OCH3), 2.62 (s, 3H, H3).

[0488] Example 55

[0489] Synthesis of 3-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid

[0490] Referring to Example 28, the yield was 45%. 1 H NMR (500MHz, DMSO-d6): δ9.78(d,J=6.0Hz,1H),7.96(s,2H),7.86(s,1H),7.52(d,J=8.3Hz,1H),7.32–7.19(m,2H),7.07(s,1H),2.50(s,3H).

[0491] Example 56

[0492] Synthesis of N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-3-methoxybenzenesulfonamide

[0493] Referring to Example 31, the yield was 47%. 1H NMR (500MHz, DMSO-d6): δ9.97(s,1H),9.76(d,J=7.0Hz,1H),7.69(s,1H),7.49(t,J=7.9Hz,1H),7 .30(d,J=7.6Hz,1H),7.28–7.19(m,4H),7.15–6.99(m,4H),3.75(s,3H),3.72(s,3H),2.52(s,3H).

[0494] Example 57

[0495] Synthesis of N-(3-(3-acetyl-inden-1-yl)-4-methoxybenzyl)benzenesulfonamide

[0496] Referring to Example 43, the yield was 68%. 1 H NMR (500MHz, CDCl3): δ9.88(d,J=7.1Hz,1H),7.93–7.84(m,2H),7.58–7.53(m,2H),7.52–7.42(m,3H),7.23(d,J=2.2 Hz,1H),7.21–7.09(m,2H),6.95–6.85(m,2H),4.79(t,J=5.9Hz,1H),4.16(d,J=6.1Hz,2H),3.81(s,3H),2.58(s,3H).

[0497] Example 58

[0498] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-(4-(tert-butyl)benzyl)-4-methoxybenzamide

[0499] Referring to Example 40, the yield was 38%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.1Hz,1H),8.95(t,J=5.8Hz,1H),8.35 (s,1H),7.87(s,1H),7.67(s,1H),7.63(d,J=9.0Hz,1H),7.44(s,1H),7.34( d,J=8.2Hz,2H),7.30–7.26(m,1H),7.26–7.15(m,4H),7.08(t,J=6.9Hz,1H) ,5.53(s,2H),4.43(d,J=5.8Hz,2H),3.81(s,3H),2.53(s,3H),1.26(s,9H).

[0500] Example 59

[0501] Synthesis of N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-cyanobenzenesulfonamide

[0502] Referring to Example 31, the yield was 42%. 1 H NMR (500MHz, DMSO-d6): δ10.27(s,1H),9.76(d,J=6.9Hz,1H),8.09(d,J=8.1Hz,2H),7.88(d ,J=8.1Hz,2H),7.69(s,1H),7.32–7.22(m,2H),7.12–7.01(m,4H),3.72(s,3H),2.52(s,3H).

[0503] Example 60

[0504] Synthesis of N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-(methylsulfonyl)benzenesulfonamide

[0505] Referring to Example 31, the yield was 49%. 1 H NMR (500MHz, DMSO-d6): δ10.31(s,1H),9.76(d,J=7.0Hz,1H),8.15(d,J=8.1Hz,2H),7.99(d,J= 8.1Hz,2H),7.71(s,1H),7.36–7.21(m,2H),7.07(m,4H),3.72(s,3H),3.27(s,3H),2.51(s,3H).

[0506] Example 61

[0507] Synthesis of N-(3-(3-acetylinden-1-yl)-4-methoxyphenyl)-4-formylbenzenesulfonamide

[0508] Referring to Example 31, the yield was 51%. 1 H NMR (500MHz, DMSO-d6): δ10.21(s,1H),10.08(s,1H),9.75(d,J=7.1Hz,1H),8.10(d,J=8.3Hz,2H),7.94(d,J=8 .2Hz,2H),7.68(s,1H),7.27(d,J=8.9Hz,1H),7.23–7.17(m,1H),7.11–6.97(m,4H),3.71(s,3H),2.51(s,3H).

[0509] Example 62

[0510] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(3-(trifluoromethyl)benzyl)benzamide

[0511] Referring to Example 40, the yield was 44%. 1 H NMR (500MHz, DMSO-d6): δ9.78(d,J=7.1Hz,1H),9.05(t,J=5.9Hz,1H),7.86(s,2H),7.70(s,1H),7.66(s,1H),7.63–7.56(m, 5H),7.26(m,1H),7.12(s,1H),7.10–7.03(m,1H),6.93(s,1H),5.47(s,2H),4.56(d,J=5.9Hz,2H),3.79(s,3H),2.53(s,3H).

[0512] Example 63

[0513] Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-(3-(hydroxymethyl)benzyl)-4-methoxybenzamide

[0514] Referring to Example 40, the yield was 43%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.1Hz,1H),9.01(t,J=5.9Hz,1H),8.35(s,1H),7.88(s,1H),7.70(s,1H),7.64(d,J=9.0Hz,1H),7. 55–7.45(m,1H),7.32–7.21(m,5H),7.19–7.15(m,2H),7.08(t,J=6.9Hz,1H),5.54(s,2H),4.50–4.45(m,4H),3.82(s,3H),2.54(s,3H).

[0515] Example 64

[0516] Synthesis of 3-(3-acetyl-inden-1-yl)-4-methoxy-N-(pyridin-3-ylsulfonyl)benzamide

[0517] Referring to Example 28, the yield was 62%. 1H NMR (500MHz, DMSO-d6): δ9.78(d,J=7.1Hz,1H),8.50(d,J=4.6Hz,1H),7.96(d,J=2.0Hz,1H),7.94–7.85(m,3H),7.7 9(s,1H),7.48(d,J=8.9Hz,1H),7.41–7.40(m,1H),7.30–7.22(m,1H),7.16–7.00(m,2H),3.80(s,3H),2.54(s,3H).

[0518] Example 65

[0519] Synthesis of 3-(3-acetyl-inden-1-yl)-N-((4-bromophenyl)sulfonyl)-4-methoxybenzamide

[0520] Referring to Example 28, the yield was 58%. 1 H NMR (500MHz, DMSO-d6): δ9.78(d,J=6.5Hz,1H),7.94(s,1H),7.90(d,J=8.4Hz,1H),7.79(s,1H),7.75(d,J=7.1Hz,2 H),7.58(d,J=7.3Hz,2H),7.48(d,J=8.7Hz,1H),7.26(t,J=7.3Hz,1H),7.16–6.93(m,2H),3.79(s,3H),2.54(s,3H).

[0521] Example 66

[0522] Synthesis of 4-methoxy-N-(benzenesulfonyl)-3-(3-propionylindoleazine-1-yl)benzamide

[0523] Referring to Examples 28 and 19, the yield was 65%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.0Hz,1H),7.95(s,1H),7.91(d,J=8.5Hz,1H),7.85–7.76(m,3H),7.48(d,J=9.0Hz, 1H),7.38–7.37(m,3H),7.28–7.21(m,1H),7.08–7.03(m,2H),3.79(s,3H),2.97(q,J=7.4Hz,2H),1.15(t,J=7.4Hz,3H).

[0524] Example 67

[0525] Synthesis of 4-methoxy-N-((4-methoxyphenyl)sulfonyl)-3-(3-propionylindoleazine-1-yl)benzamide

[0526] Referring to Example 66, the yield was 63%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.0Hz,1H),7.94(s,1H),7.89(d,J=8.7Hz,1H),7.79(s,1H),7.76(d,J=8.1Hz,2H),7.48(d,J=9.0Hz, 1H),7.30–7.20(m,1H),7.07–7.03(m,2H),6.89(d,J=8.2Hz,2H),3.78(s,3H),3.77(s,3H),2.97(q,J=7.2Hz,2H),1.15(t,J=7.3Hz,3H).

[0527] Example 68

[0528] Synthesis of 3-(3-acetyl-inden-1-yl)-N-((4-bromophenyl)sulfonyl)-5-methoxybenzamide

[0529] Referring to Example 28, the yield was 22%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.0Hz,1H),8.01(s,1H),7.92(d,J=8.9Hz,1H),7.77(d,J=8.4Hz,3H),7.6 0(d,J=8.4Hz,2H),7.41(s,1H),7.39–7.33(m,1H),7.20(s,1H),7.11–7.08(m,1H),3.84(s,3H),2.58(s,3H).

[0530] Example 69

[0531] Synthesis of 3-(3-acetyl-inden-1-yl)-N-((4-acetylphenyl)sulfonyl)-5-methoxybenzamide

[0532] Referring to Example 28, the yield was 38%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.1Hz,1H),8.16(q,J=8.5Hz,4H),8.09(s,1H),8.01(d,J=9.0Hz ,1H),7.75(s,1H),7.50–7.31(m,3H),7.11(t,J=6.9Hz,1H),3.88(s,3H),2.65(s,3H),2.58(s,3H).

[0533] Example 70

[0534] Synthesis of 3-(3-acetyl-inden-1-yl)-5-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide

[0535] Referring to Example 28, the yield was 44%. 1 H NMR (500MHz, DMSO-d6): δ12.79(s,1H),9.80(d,J=7.1Hz,1H),8.14(s,1H),8.10(s,1H),8.04–8.01(m,2H),7.97(d,J=8.1H z,1H),7.75(s,1H),7.64(t,J=8.0Hz,1H),7.44(s,1H),7.42–7.33(m,2H),7.11(t,J=6.8Hz,1H),3.88(s,3H),2.57(s,3H).

[0536] Example 71

[0537] Synthesis of 3-(3-acetyl-inden-1-yl)-N-(3,5-dichlorophenyl)sulfonyl)-5-methoxybenzamide

[0538] Referring to Example 28, the yield was 55%. 1 H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.1Hz,1H),8.11(s,1H),8.08(s,1H),8.04(d,J=9.0Hz,1H),7.99(d,J=1 .6Hz,2H),7.77(s,1H),7.45(s,1H),7.39(t,J=7.7Hz,2H),7.12(t,J=6.9Hz,1H),3.90(s,3H),2.58(s,3H).

[0539] Example 72

[0540] Synthesis of 3-methoxy-N-(benzenesulfonyl)-5-(3-propionylindoleazine-1-yl)benzamide

[0541] Referring to Example 66, the yield was 55%. 1H NMR (500MHz, DMSO-d6): δ12.66(s,1H),9.84(d,J=7.1Hz,1H),8.11(s,1H),8.06–7.99(m,3H),7.78–7.71(m,2H),7.67(t,J= 7.7Hz,2H),7.43(s,1H),7.40–7.31(m,2H),7.10(t,J=6.8Hz,1H),3.88(s,3H),3.00(q,J=7.4Hz,2H),1.16(t,J=7.4Hz,3H).

[0542] Example 73

[0543] N-((4-acetylphenyl)sulfonyl)-3-methoxy-5-(3-propionylindoleazine-1-yl)benzamide

[0544] Referring to Example 66, the yield was 58%. 1 H NMR (500MHz, DMSO-d6): δ12.85(s,1H),9.84(d,J=7.1Hz,1H),8.18(q,J=8.6Hz,4H),8.12(s,1H),8.03(d,J=9.0Hz,1H),7.74(s,1 H),7.45(s,1H),7.39–7.35(m,2H),7.11(t,J=6.9Hz,1H),3.89(s,3H),3.01(q,J=7.4Hz,2H),2.66(s,3H),1.17(t,J=7.4Hz,3H).

[0545] Example 74

[0546] 3-(3-acetyl-inden-1-yl)-5-methoxy-N-(benzenesulfonyl)benzamide

[0547] Referring to Example 28, the yield was 44%. 1 H NMR (500MHz, DMSO-d6): δ12.68(s,1H),9.80(d,J=7.1Hz,1H),8.09(s,1H),8.05–8.01(m,3H),7.76–7.73( m,2H),7.68–7.65(m,2H),7.42(s,1H),7.41–7.32(m,2H),7.10(t,J=6.6Hz,1H),3.88(s,3H),2.57(s,3H).

[0548] Example 75

[0549] 3-(3-acetyl-inden-1-yl)-5-methoxy-N-(methylsulfonyl)benzamide

[0550] Referring to Example 28, the yield was 36%. 1 H NMR (500MHz, DMSO-d6): δ12.25(s,1H),9.83(d,J=7.1Hz,1H),8.13(s,1H),8.08(d,J=9.0Hz,1H),7.81 (s,1H),7.47(s,1H),7.44–7.40(m,2H),7.13(t,J=6.7Hz,1H),3.92(s,3H),3.42(s,3H),2.60(s,3H).

[0551] Example 76

[0552] N-(3-(3-acetylinden-1-yl)-5-methoxybenzyl)methanesulfonamide

[0553] Referring to Example 43, the yield was 68%. 1 H NMR (500MHz, CDCl3): δ9.91(d,J=7.1Hz,1H),7.83(d,J=9.0Hz,1H),7.61(s,1H),7.24–7.18(m,1H),7.15(s,1H),7.06(s,1 H),6.92(t,J=6.6Hz,1H),6.85(s,1H),4.77(d,J=5.7Hz,1H),4.38(d,J=6.1Hz,2H),3.88(s,3H),2.95(s,3H),2.61(s,3H).

[0554] Example 77

[0555] Synthesis of N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0556] Step 1: Synthesis of 1-(1-(2-amino-5-methoxyphenyl)-indene-3-yl)ethyl-1-one

[0557] Referring to Example 1, the yield was 62%. 1 H NMR(500MHz,DMSO)δ9.78(d,J=7.1Hz,1H),7.82(s,1H),7.53(d,J=8.9Hz,1H),7.28–7.25(m ,1H),7.06(td,J=6.9,1.1Hz,1H),6.77–6.72(m,3H),4.40(s,2H),3.68(s,3H),2.54(s,3H).

[0558] Step 2: Synthesis of N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0559] Referring to Example 57, the yield was 66%. 1 H NMR(500MHz, CDCl3)δ9.83(d,J=7.1Hz,1H),7.70(d,J=8.9Hz,1H),7.50–7.38(m,3H),7.28–7.25(m,2H),7.1 4–7.01(m,2H),7.00–6.89(m,2H),6.86(s,1H),6.72(d,J=3.0Hz,1H),6.45(s,1H),3.80(s,3H),2.48(s,3H).

[0560] Example 78

[0561] Synthesis of 2-((1H-imidazol-1-yl)methyl)-N-benzyl-4-methoxy-5-(3-neovalerylindoleazine-1-yl)benzamide

[0562] Referring to Example 41, the yield was 21%. 1 H NMR (500MHz, CDCl3) δ9.99(d,J=7.2Hz,1H),7.89(s,1H),7.77(s,1H),7.54(s,1H),7.46(d,J=8.9Hz,1H),7.36-7.31(m,3H),7. 14-7.09(m,3H),6.87(t,J=6.8Hz,1H),6.76(s,1H),6.31(s,1H),5.50(s,2H),4.54(d,J=5.5Hz,2H),3.81(s,3H),1.45(s,9H).

[0563] Example 79

[0564] Synthesis of N-(3-(3-isobutylinden-1-yl)-4-methoxyphenyl)benzenesulfonamide

[0565] Referring to Examples 41 and 77, the yield was 42%. 1H NMR (500MHz, DMSO) δ9.98(s,1H),9.83(d,J=7.1Hz,1H),7.76(d,J=7.7Hz,2H),7.72(s,1H),7.67(t,J=7.3Hz,1H),7.59( t,J=7.6Hz,2H),7.29–7.22(m,2H),7.10–7.01(m,4H),3.72(s,3H),3.51(dp,J=13.8,6.9Hz,1H),1.17(d,J=6.7Hz,6H).

[0566] Example 80

[0567] Synthesis of N-(4-methoxy-3-(3-neovalerindolazin-1-yl)phenyl)benzenesulfonamide

[0568] Referring to Example 79, the yield was 38%. 1 H NMR(500MHz,DMSO)δ9.98(s,1H),9.86(d,J=7.2Hz,1H),7.75(d,J=7.5Hz,2H),7.72(s,1H),7.67(t,J=7.4Hz,1H ),7.59(t,J=7.6Hz,2H),7.24(d,J=3.0Hz,2H),7.10–7.07(m,1H),7.07–6.97(m,3H),3.72(s,3H),1.38(s,9H).

[0569] Example 81

[0570] Synthesis of N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)pyridine-2-sulfonamide

[0571] Referring to Example 77, the yield was 58%. 1 H NMR(500MHz, CDCl3)δ9.83(d,J=7.1Hz,1H),8.62(s,1H),8.59(d,J=4.8Hz,1H),7.69–7.59(m,2H),7.15–7.08(m,2H) ,7.04(d,J=8.8Hz,1H),7.00(s,1H),6.98–6.90(m,2H),6.75(d,J=2.8Hz,1H),6.68(s,1H),3.81(s,3H),2.52(s,3H).

[0572] Example 82

[0573] Synthesis of N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-formylbenzenesulfonamide

[0574] Referring to Example 77, the yield was 56%. 1 H NMR(500MHz, CDCl3)δ9.92(s,1H),9.80(d,J=6.9Hz,1H),7.67–7.62(m,3H),7.51(d,J=7.9Hz,2H),7.2 6(s,1H),7.07–6.93(m,4H),6.89(t,J=5.9Hz,1H),6.74(s,1H),6.70(s,1H),3.81(s,3H),2.50(s,3H).

[0575] Example 83

[0576] Synthesis of 3-(3-acetyl-8-ethylinden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0577] Referring to Example 28, the yield was 33%. 1 H NMR(500MHz,DMSO)δ12.42(s,1H),9.74(d,J=5.4Hz,1H),8.00–7.97(m,3H),7.89(s,1H),7.72(brs,1H), 7.66–7.59(m,3H),7.20(d,J=8.4Hz,1H),7.07–6.97(m,2H),3.75(s,3H),2.38(brs,2H),0.84(brs,3H).

[0578] Example 84

[0579] Synthesis of 3-(3-acetyl-8-isopropyl-inden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0580] Referring to Example 28, the yield was 36%. 1 H NMR(500MHz,DMSO)δ9.75(d,J=6.9Hz,1H),7.94(dd,J=8.6,1.8Hz,1H),7.90–7.79(m,3H),7.52(s,1H),7.38–7.37(m,3H),7.14(d,J =7.1Hz,1H),7.09–6.97(m,2H),3.67(s,3H),2.98(dt,J=13.5,6.7Hz,1H),2.49(s,3H),1.06(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).

[0581] Example 85

[0582] Synthesis of 3-(3-acetyl-6-ethylinden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0583] Referring to Example 28, the yield was 42%. 1 H NMR (500MHz, DMSO) δ9.66(s,1H),7.95(d,J=1.8Hz,1H),7.93–7.88(m,1H),7.84(d,J=6.0Hz,2H),7.73(s,1H),7.44–7. 40(m,4H),7.21(d,J=9.5Hz,1H),7.08(d,J=8.6Hz,1H),3.79(s,3H),2.66(q,J=15.0,7.5Hz,2H),1.24(t,J=7.5Hz,3H).

[0584] Example 86

[0585] Synthesis of 3-(3-acetyl-6-isopropyl-inden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide

[0586] Referring to Example 28, the yield was 34%. 1 H NMR (500MHz, DMSO) δ9.69(s,1H),7.95(d,J=2.0Hz,1H),7.90(dd,J=8.6,2.0Hz,1H),7.83(dd,J=6.5,3.0Hz,2H),7.73(s,1H),7.44(d,J= 9.2Hz,1H),7.39–7.36(m,3H),7.30–7.21(m,1H),7.07(d,J=8.7Hz,1H),3.79(s,3H),3.03–2.88(m,1H),2.52(s,3H),1.29–1.25(m,6H).

[0587] Example 87

[0588] Synthesis of 1-(7-(benzyloxy)-1-(2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0589] Referring to Example 21, the yield was 60%. 1H NMR (500MHz, DMSO) δ9.70(d,J=7.6Hz,1H),7.76(s,1H),7.47(d,J=7.5Hz,2H),7.41(t,J=7.3Hz,2H),7.35(t,J=7.2 Hz,1H),7.06(d,J=8.8Hz,1H),6.95(s,1H),6.94–6.84(m,3H),5.19(s,2H),3.76(s,3H),3.68(s,3H),2.48(s,3H).

[0590] Example 88

[0591] Synthesis of 1-(7-(benzyloxy)-1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-indene-3-yl)ethyl-1-one

[0592] Referring to Example 21, the yield was 29%. 1 H NMR (500MHz, DMSO) δ9.70(d,J=7.7Hz,1H),7.75(s,1H),7.45(d,J=7.4Hz,2H),7.40(t,J=7.5Hz,2H),7.34(t,J=7.1Hz,1H),7.17(s,1H),6.93(s,1H) ,6.91(d,J=2.4Hz,1H),6.86(dd,J=7.7,2.5Hz,1H),5.18(s,2H),5.10(t,J =5.5Hz,1H),4.55(d,J=5.4Hz,2H),3.75(s,3H),3.67(s,3H),2.48(s,3H).

[0593] Example 89

[0594] Synthesis of 1-(1-(pyridin-2-yl)azinden-3-yl)aceto-1-one

[0595] Dissolve 1-(2-oxopropyl)pyridine ammonium chloride (171.62 g, 1.00 g, 5.82 mmol, 2 eq) in dichloromethane. Slowly add triethylamine (101.19 g, 1.00 mL, 7.27 mmol, 1 eq) under ice bath conditions. The system turns yellow. Then add 2-alkynylpyridine (103.12 g, 0.28 mL, 2.91 mmol, 1 eq) and react overnight at room temperature. After the reaction is complete, concentrate under vacuum, extract with ethyl acetate / saturated NaCl solution, back-extract once with dichloromethane, dry to anhydrous sodium sulfate, and then perform column chromatography (petroleum ether:ethyl acetate = 10:1) to give a white solid product, 1-(1-(pyridin-2-yl)indend-3-yl)ethyl-1-one (236.27 g, 200 mg, 0.85 mmol, 29%). 1H NMR (500MHz, DMSO-d6): δ9.81(d,J=7.0Hz,1H),8.85(d,J=9.0Hz,1H),8.62(d,J=4.2Hz,1H),8.42(s,1H),7.97(d,J= 8.0Hz,1H),7.83(t,J=7.7Hz,1H),7.42(t,J=7.8Hz,1H),7.23–7.18(m,1H),7.13(t,J=6.8Hz,1H),2.59(s,3H,CH3).

[0596] Example 90

[0597] Synthesis of 1-(1-(3,6-dimethoxypyridin-2-yl)azind-3-yl)aceto-1-one

[0598] Step 1: Synthesis of 2-bromo-6-methoxypyridine-3-ol

[0599] Compound 6-methoxypyridine-3-ol (125.13 g, 1.00 g, 7.99 mmol, 1 eq) was dissolved in acetonitrile, and NBS (177.98 g, 1.56 g, 8.79 mmol, 1.1 eq) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was complete, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated Na₂S₂O₃ solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under vacuum to give crude product 2-15 (204.02 g, 200 mg, 0.98 mmol, 12%).

[0600] 1 H NMR (400MHz, CDCl3) δ: 3.9 (s, 3H, OCH3), 5.0 (brs, 1H, OH), 6.7 (d, 1H, J = 8.6Hz, Ar-H), 7.3 (d, 1H, J = 8.6Hz, Ar-H).

[0601] Step 2: Synthesis of 2-bromo-3,6-dimethoxypyridine

[0602] 2-Bromo-6-methoxypyridine-3-ol (204.02 mg, 200 mg, 0.98 mmol, 1 eq) was dissolved in acetonitrile, and K₂CO₃ (138.2 mg, 406 mg, 2.94 mmol, 3 eq) and CH₃I (141.94 mg, 0.12 mL, 1.96 mmol, 2 eq) were added. The mixture was reacted overnight at room temperature. After the reaction was completed, the solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate / saturated NaCl solution, back-extracted once with dichloromethane, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether:ethyl acetate = 15:1) to give product 2-16 (218.05 mg, 185 mg, 0.91 mmol, 93%). 1H NMR (500MHz, CDCl3): δ7.26 (d, J = 9Hz, 1H, Ar-H), 6.68 (d, J = 8.5Hz, 1H, Ar-H), 3.89 (s, 1H, OCH3), 3.85 (s, 1H, OCH3).

[0603] Step 3: Synthesis of 1-(1-(3,6-dimethoxypyridin-2-yl)azind-3-yl)aceto-1-one

[0604] Referring to Example 1, the yield was 22%. 1 H NMR (500MHz, CDCl3): δ9.95(d,J=7.0Hz,1H,Ar-H),8.76(d,J=9.0Hz,1H,Ar-H),8.28(s,1H,Ar-H),7.34(d,J=8.8Hz,1H,Ar-H),7.26( t,J=7.8Hz,1H,Ar-H),6.96(t,J=6.8Hz,1H,Ar-H),6.62(d,J=8.8Hz,1H,Ar-H),4.02(s,3H,CH3),3.91(s,3H,OCH3),2.62(s,3H,CH3).

[0605] Example 91

[0606] Synthesis of 1-(1-(4-methoxy-3,5-dimethylphenyl)azind-3-yl)ethyl-1-one

[0607] Referring to Example 1, the yield was 55%. 1 H NMR(500MHz, CDCl3)δ9.93(d,J=6.9Hz,1H),7.84(d,J=8.9Hz,1H),7.58(s,1H),7.28–7.2 4(m,2H),7.22–7.17(m,1H),6.92(t,J=6.7Hz,1H),3.81(s,3H),2.62(s,3H),2.39(s,6H).

[0608] Example 92

[0609] Synthesis of 1-(1-phenylindendene-3-yl)ethyl-1-one

[0610] Referring to Example 1, the yield was 62%. 1H NMR (500MHz, CDCl3): δ9.92(d,J=7.1Hz,1H),7.84(d,J=9.0Hz,1H),7.62(s,1H),7.59(d,J=7.2Hz,2H),7 .47(t,J=7.7Hz,2H),7.33(t,J=7.4Hz,1H),7.21–7.16(m,1H),6.91(t,J=6.9Hz,1H),2.61(s,3H,COCH3).

[0611] Example 93

[0612] Synthesis of 1-(1-(3-(hydroxymethyl)phenyl)-indene-3-yl)ethyl-1-one

[0613] Referring to Example 1, the yield was 61%. 1 H NMR (500MHz, CDCl3): δ9.90 (d, J=7.1Hz, 1H, Ar-H), 7.83 (d, J=8.9Hz, 1H, Ar-H ),7.62(s,1H,Ar-H),7.60(s,1H,Ar-H),7.51(d,J=7.6Hz,1H,Ar-H),7.45(t, J=7.5Hz,1H,Ar-H),7.32(d,J=7.4Hz,1H,Ar-H),7.21–7.14(m,1H,Ar-H),6.9 0(t,J=6.9Hz,1H,Ar-H),4.79(s,2H,CH2),2.59(s,3H,CH3),2.08(s,1H,OH).

[0614] Example 94

[0615] Synthesis of 1-(1-(2-chlorophenyl)-indene-3-yl)ethyl-1-one

[0616] The synthesis method is the same as in Example 1, with a yield of 42%. 1 H NMR (500MHz, DMSO-d6): δ9.79(d,J=7.0Hz,1H,Ar-H),7.89(s,1H,Ar-H),7.62(d,J=7.6Hz,1H,Ar-H),7.53(d,J=7 .2Hz,1H,Ar-H),7.45(m,3H,3×Ar-H),7.30(t,J=7.8Hz,1H,Ar-H),7.09(t,J=6.8Hz,1H,Ar-H),2.54(s,3H,CH3).

[0617] Example 95

[0618] Synthesis of 1-(1-(3-(trifluoromethyl)phenyl)indoleazin-3-yl)ethyl-1-one

[0619] The synthesis method is the same as in Example 1, with a yield of 55%. 1 H NMR (500MHz, DMSO-d6): δ9.82(d,J=7.1Hz,1H,Ar-H),8.19(s,1H,Ar-H),8.02–7.95(m,3H,3×Ar-H),7.71(t,J=7.7 Hz,1H,Ar-H),7.66(d,J=7.8Hz,1H,Ar-H),7.42–7.36(m,1H,Ar-H),7.12(t,J=6.5Hz,1H,Ar-H),2.59(s,3H,CH3).

[0620] Example 96

[0621] Synthesis of 1-(1-(2-methoxyphenyl)-indene-3-yl)ethyl-1-one

[0622] The synthesis method is the same as in Example 1, with a yield of 58%. 1 H NMR (500MHz, CDCl3) δ9.90(d,J=7.1Hz,1H,Ar-H),7.65(s,1H,Ar-H),7.57(d,J=8.9Hz,1H,Ar-H),7.43(dd,J=7.4,1.6Hz,1H,Ar-H),7.38–7.32(m,1 H,Ar-H),7.15(dd,J=8.2,7.4Hz,1H,Ar-H),7.06(dd,J=15.0,7.8Hz,2H,2×Ar-H),6.90(t,J=6.9Hz,1H,Ar-H),3.84(s,3H,OCH3),2.61(s,3H,CH3).

[0623] Example 97

[0624] Synthesis of 1-(1-(3-methoxyphenyl)-indene-3-yl)ethyl-1-one

[0625] The synthesis method is the same as in Example 1, with a yield of 51%. 1H NMR (500MHz, CDCl3) δ9.91(d,J=7.1Hz,1H,Ar-H),7.86(d,J=8.9Hz,1H,Ar-H),7.62(s,1H,Ar-H),7.39(t,J=7.9Hz,1H,Ar-H),7.19(dd,J=15.5,7. 3Hz,2H,2×Ar-H),7.12(d,J=2.0Hz,1H,Ar-H),6.92(t,J=6.8Hz,1H,Ar-H),6.88(dd,J=8.2,2.2Hz,1H,Ar-H),3.88(s,3H,OCH3),2.61(s,3H,CH3).

[0626] Bioactivity test

[0627] I. In vitro binding experiment

[0628] 1. Thermal Stability Shift Assay (TSA)

[0629] Experimental objective: To determine the protein-stabilizing ability after binding using the TSA assay, and the experimental results are expressed by ΔT. m (°C) is presented when ΔT m The higher the value, the stronger the ability of the compound to stabilize the protein after binding, and the stronger the protein binding ability.

[0630] Experimental Methods: The stock solutions of different components were diluted to appropriate loading concentrations, and then 20 μL of the reaction mixture was added, including 2 μL of protein, 2 μL of SYPRO Orange fluorescent dye, 10 μL of the compound, 2 μL of buffer (10× buffer: 100 mM HEPES, 1500 mM NaCl, 50% (v / v) glycerol, diluted with deionized water to 50 mL, pH 7.5), and 4 μL of deionized water. The mixture was thoroughly mixed and added to a 96-well plate. The plate was centrifuged at 1000 rpm for 1 min at room temperature and incubated on ice for 30 min. The incubated 96-well plate was then placed in a real-time quantitative PCR instrument, with the temperature program set to 20℃–80℃, with temperature changes at 0.3℃ intervals, and readings taken every 5 seconds. The data was saved and analyzed. Comparative Examples 1 and 2 are known highly effective inhibitors of the BRD7 / 9 bromodomain.

[0631] The experimental results are shown in Table 2:

[0632] Table 2. TSA test results of the compounds in the comparative and example examples within the BRD7 / BRD9 bromine domain. Note: In the TSA experiment, ΔT m<1℃ generally indicates that the sample has not bound to the target protein, and is represented by "-"; 1℃≤ΔT m <3℃ generally indicates a weak binding to the target protein, denoted as "+"; 3℃≤ΔT m <6℃ is generally considered to indicate that the sample has a moderate binding strength to the target protein, denoted as "++"; ΔT m ≥6℃ generally indicates that the example has a strong binding to the target protein, indicated by "+++"; NT: Not tested.

[0633] According to the results in Table 2, most of the compounds in Table 2 have strong binding activity with BRD7 and BRD9.

[0634] 2. HTRF Experiment

[0635] Experimental Objective: To determine the inhibitory IC50 of a compound on the enzyme binding reaction of the BRD9 bromine domain using homogeneous time-resolved fluorescence (HTRF). 50 value.

[0636] Experimental method: The test compound was started at 1 μM and serially diluted 3 times, BRD9:bBRD9i = 10:40 nM, where bBRD9i is a self-synthesized biotin molecule. 1×Buffer: 20 mM HEPES, 150 mM NaCl, 5 mM dithiothreitol (DTT), 0.005% Tween 20, 100 μg / mL bovine serum albumin (BSA), pH adjusted to 7.5. The total volume of the test was 20 μL, and the test was performed using a PerkinElmer Envision microplate reader. The specific operation steps are as follows: (1) Add 4 μL of 5× compound solution to each well (replace with 1×Buffer if no compound is available). Add 2 μL of 10× protein solution to each well. (2) Centrifuge at 1000 rpm for 1 min and incubate on ice for 30 min. (3) Add 2 μL of 10× probe solution to each well. (4) Add 2 μL of 1M KF solution to each well. (5) Centrifuge at 1000 rpm for 1 min. (6) Add 10 μL of detection solution, centrifuge at 1000 rpm for 1 min, gently vortex for 3–5 min to mix, and incubate on ice for 60 min. The detection solution includes Anti HIS-Eu cryptate donor magnetic beads (Cat#61HISKLB) and Streptavadin-XL665 acceptor beads (Cat#610SAXLF) diluted 1:400.

[0637] The experimental results are shown in Table 3:

[0638] Table 3. HTRF activity test data for Comparative Example 1 and Example 2 Note: The binding activity of the compound to the bromine domains of BRD7 and BRD9 was tested using the HTRF method. Less than 0.3 μM is considered strong activity, expressed as a specific value; 0.3-1 μM is considered moderate activity; 1-5 μM is considered weak activity; greater than 5 μM indicates almost no binding activity; NT: not tested.

[0639] As can be seen from Table 3, Examples 1-2, 12-15 and 19-20 all have strong binding activity to the bromine domain of BRD9, while Examples 1 and 19-20 have strong binding activity to BRD7.

[0640] II. In vitro cell proliferation inhibition experiment

[0641] Experimental objective: To evaluate the antitumor cell proliferation activity of the compounds of this invention using CellTiter-Glo assay reagent.

[0642] Experimental Methods: MV4-11, EOL-1, and Kasumi-1 cells were suspended in RPMI 1640 medium containing 10% FBS and cultured at 37°C in a 5% CO2 incubator. Each cell type was passaged at least twice after resuscitation before use. Cells were seeded at 500-1000 cells per well in 384-well plates. For adherent cells: each well contained 20 μL of medium and was cultured in a cell culture incubator for 12 hours. Then, 10 μL of the compound was added to each well, with three replicates for each concentration. For suspension cells, the test compound was added directly without a 12-hour culture period. For EOL-1 and Kasumi-1 cells, the compound was incubated with the cells for 72 hours before testing; for MV4-11 cells, the compound was incubated with the cells for 120 hours before testing. During testing: Add 25 μL of CellTiter-GLO reagent (Promega) and measure the fluorescence signal using a GLOMAX microplate spectrophotometer (Promega) according to the manufacturer's instructions. Calculate the maximum half-maximal inhibitory concentration (IC50) using GraphPad Prism 6 software. 50 )value.

[0643] 1. The results of the inhibitory experiments of the compound on acute myeloid leukemia cells EOL-1 and Kasumi-1 at a concentration of 20 μM are shown in Table 4.

[0644] Table 4. Results of single-point inhibition experiments of compounds at 20 μM concentration. Note: The growth inhibition rate of compounds at 20 μM concentration on acute myeloid leukemia cells EOL-1 and Kasumi-1 is shown. An inhibition rate of more than 70% indicates good cell inhibitory activity. NT: Not tested.

[0645] According to the results in Table 4, the compounds of the present invention in Examples 3-9, 11-14, and 16-17 exhibited good inhibitory activity against the proliferation of EOL-1 and Kasumi-1 cells at a concentration of 20 μM. Example 10 also showed good inhibitory activity against the proliferation of Kasumi-1 cells at a concentration of 20 μM. All the compound examples showed superior inhibitory activity against the proliferation of EOL-1 and Kasumi-1 cells at a concentration of 20 μM compared to the positive control compound, Comparative Example 1.

[0646] 2. Results of in vitro proliferation inhibition experiments of the compound on MV4-11 cells

[0647] Table 5 Results of in vitro cell proliferation inhibition experiments of the compounds Note: The compound's anti-cancer cell proliferation inhibitory activity against acute myeloid leukemia cells MV4-11 is as follows: less than 5 μM indicates strong activity, expressed as a specific value; 5-10 μM indicates moderate activity; 10-20 μM indicates weak activity; and greater than 20 μM indicates almost no anti-cell proliferation inhibitory activity.

[0648] According to the results in Table 5, most of the compounds in the table showed strong inhibitory activity against the proliferation of MV4-11 cells. Among them, Examples 1, 3, 5, 7, 12, 20, 22, 25, 26, 45, 46-49, 51-53, and 90 exhibited superior inhibitory activity against the proliferation of MV4-11 cells compared to the positive control compounds, Comparative Examples 1 and 2.

[0649] 3. Inhibitory activity of the compound on the proliferation of other tumor cells

[0650] Table 6. Proliferation-inhibiting activity of the examples on other tumor cells. Note: The anti-cancer cell proliferation inhibitory activity of the compound against different cancer cells is as follows: less than 5 μM is strong activity, expressed as a specific value; 5-10 μM is moderate activity; 10-20 μM is weak activity; greater than 20 μM indicates almost no anti-cell proliferation inhibitory activity; NT: not tested.

[0651] According to the results in Table 5, Example 1 showed strong inhibitory activity against human multiple myeloma cells MM.1S, Example 12 showed strong inhibitory activity against human malignant melanoma cells A375 and human multiple myeloma cells MM.1S, and Example 54 showed strong inhibitory activity against prostate cancer cells 22Rv1.

[0652] The applicant declares that the present invention illustrates the indazine compounds and their applications through the above embodiments, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0653] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0654] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. An indazine compound, characterized in that, The indazine compounds have the structure shown in Formula I: X1 and X2 are selected from C or N; R1 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, and 0-3 Rs. 10 Substituted amino groups; R2 and R4 are each selected from hydrogen, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C3-C7 cycloalkyl, -COR9, 0-3 R 10 Substituted amino groups, 0-3 R groups 10 Substituted amino C1-C3 alkyl, -CONH-R 11 R9 is selected from hydroxyl and alkoxy groups; R 10 and R 11 Each of the following is selected from C1-C5 alkyl, C3-C7 cycloalkyl, benzyl, -SO2-C1-C5 alkyl, -SO2-C1-C5 alkoxy, -SO2-C6-C10 aryl substituted by one or more substituents, and 5-10 heteroaryl groups containing a carbon atom and 1-4 heteroatoms selected from N, O and S substituted by one or more substituents; R3 is selected from hydrogen, aldehyde, acetyl, and -YR. 12 Where Y is selected from -CH(CH3)2- and -(CH2). n -、-CO-;R 12 Selected from hydroxyl groups, 0-3 R groups 13 A substituted amino group; a 5-10 membered heterocyclic group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; a 5-10 membered heteroaryl group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; R 13 Selected from C1-C5 alkyl groups, and selected from n being 1-5; R5 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, -OR 14 ;R 14 Selected from hydrogen, benzyl, -SO2-C1-C5 alkyl, -CONH-R 15 ;R 15 Selected from 0-3 C1-C5 alkyl groups; R6 is selected from hydrogen, C1-C5 alkyl groups, and -COR. 16 ;R 16 Selected from C1-C5 alkyl and C3-C7 cycloalkyl groups with 0-3 halogen substitutions; R7 and R8 are selected from hydrogen and C1-C5 alkyl groups.

2. An indazine compound, characterized in that, The indazine compounds have the structure shown in Formula II: X1 is selected from C or N; R1 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, 0-3 Rs 10 Substituted amino groups; R2 and R4 are each selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C3-C7 cycloalkyl, -COR9, 0-3 R groups. 10 Substituted amino groups, 0-3 R groups 10 Substituted amino C1-C3 alkyl, -CONH-R 11 R9 is selected from hydroxyl and alkoxy groups; R 10 and R 11 Each of the following is selected from C1-C5 alkyl, C3-C7 cycloalkyl, benzyl, -SO2-C1-C5 alkyl, -SO2-C1-C5 alkoxy, -SO2-C6-C10 aryl substituted by one or more substituents, and 5-10 heteroaryl groups containing a carbon atom and 1-4 heteroatoms selected from N, O and S substituted by one or more substituents; R3 is selected from hydrogen, aldehyde, acetyl, and -YR. 12 Where Y is selected from -CH(CH3)2- and -(CH2). n -、-CO-;R 12 Selected from hydroxyl groups, 0-3 R groups 13 A substituted amino group; a 5-10 membered heterocyclic group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; a 5-10 membered heteroaryl group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; R 13 Selected from C1-C5 alkyl groups, and selected from n being 1-5; R5 is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, -OR 14 ;R 14 Selected from hydrogen, benzyl, -SO2-C1-C5 alkyl, -CONH-R 15 ;R 15 Selected from 0-3 C1-C5 alkyl groups; R6 is selected from hydrogen, C1-C5 alkyl groups, and -COR. 16 ;R 16 Selected from C1-C5 alkyl and C3-C7 cycloalkyl groups; R7 and R8 are selected from hydrogen and C1-C5 alkyl groups.

3. The indazine compound according to claim 1 or claim 2, characterized in that, The indazine compounds have the structure shown in Formula III: X1 is selected from C or N; R1 is selected from hydrogen, C1-C5 alkoxy groups, and 0-3 R groups. 10 Substituted amino groups; R2 and R4 are each selected from hydrogen, C1-C5 alkoxy groups, -COR9, and 0-3 R groups. 10 Substituted amino groups, 0-3 R groups 10 Substituted amino C1-C3 alkyl, -CONH-R 11 R9 is selected from hydroxyl and alkoxy groups; R 10 and R 11 Each is selected from C1-C5 alkyl, C3-C7 cycloalkyl, benzyl, -SO2-C1-C5 alkyl, -SO2-C6-C10 aryl groups substituted by one or more substituents; R3 is selected from hydrogen, -YR 12 Where Y is selected from -CH(CH3)2- and -(CH2). n -、-CO-;R 12 Selected from hydroxyl groups, 0-3 R groups 13 A substituted amino group; a 5-10 membered heterocyclic group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; a 5-10 membered heteroaryl group comprising a carbon atom and 1-4 heteroatoms selected from N, O, and S substituted by one or more substituents; R 13 Selected from C1-C5 alkyl groups, and n is 1-5, preferably, R 12 It is imidazole, morpholino, pyrazol, or thiazolyl; R5 is selected from hydrogen, C1-C5 alkoxy group, and -OR. 14 ;R 14 Selected from hydrogen, benzyl, -SO2-C1-C5 alkyl, -CONH-R 15 ;R 15 Selected from 0-3 C1-C5 alkyl groups; R 16 Selected from C1-C5 alkyl and C3-C7 cycloalkyl. Preferably, R 16 The compounds are methyl, ethyl, isopropyl, and cyclopropyl. R7 and R8 are selected from hydrogen and C1-C5 alkyl groups.

4. The indazine compound according to any one of claims 1-3, characterized in that, The indazine compound is any one of the following compounds: 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)indene-3-yl)ethane-1-one 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-2,5-dimethoxyphenyl)indene-3-yl)ethane-1-one 1-(1-(2,5-dimethoxy-4-(methoxymethyl)phenyl)indolinazine-3-yl)ethyl-1-one 1-(1-(4-((3-hydroxyazacyclobutane-1-yl)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one 1-(1-(4-((diethylamino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N,N-dimethylbenzamide 1-(1-(3-amino-4-((dimethylamino)methyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one 1-(1-(3-(dimethylamino)-4-(hydroxymethyl)-5-methoxyphenyl)indoleazine-3-yl)ethyl-1-one 4-(3-acetylindoleazine-1-yl)-2,5-dimethoxy-N-methylbenzamide 1-(1-(2,5-dimethoxy-4-(morpholin-4-carbonyl)phenyl)indoleazine-3-yl)ethyl-1-one 1-(1-(4-(2-hydroxypropyl-2-yl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)acet-1-one 1-(1-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one 1-(1-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one 1-(1-(2,5-dimethoxy-4-(morpholinomethyl)phenyl)inden-3-yl)ethane-1-one 1-(1-(4-((ethyl(methyl)amino)methyl)-3,5-dimethoxyphenyl)indoleazine-3-yl)ethyl-1-one 4-(3-Acetindolazin-1-yl)-2,6-dimethoxy-N,N-dimethylbenzamide 1-(1-(3-(dimethylamino)-4-((dimethylamine)methyl)-5-methoxyphenyl)indene-3-yl)ethane-1-one 1-(1-(4-((1H-imidazol-1-yl)methyl)-3,5-dimethoxyphenyl)indene-3-yl)prop-1-one 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)indene-3-yl)prop-1-one 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-(benzyloxy)azind-3-yl)ethane-1-one 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-hydroxy-indene-3-yl)ethane-1-one 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-indene-7-yl dimethylcarbamate 1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-3-acetyl-indene-7-ylmethanesulfonate 1-(1-(4-((1H-imidazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxyindene-3-yl)ethane-1-one 1-(1-(4-((1H-pyrazol-1-yl)methyl)-2,5-dimethoxyphenyl)-7-methoxyindene-3-yl)ethane-1-one 1-(1-(2,5-dimethoxy-4-((2-thio-1,3,4-thiadiazol-3(2H)-yl)methyl)phenyl)-7-methoxy-indene-3-yl)ethane-1-one 3-(3-acetylindololin-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide 3-(3-acetylindololin-1-yl)-4-methoxy-N-(methylsulfonyl)benzamide 3-(3-acetyl-inden-1-yl)-N-cyclopropyl-5-methoxybenzamide N-(3-(3-acetylindololin-1-yl)-4-methoxyphenyl)benzenesulfonamide 3-(3-acetyl-inden-1-yl)-N-((4-acetylphenyl)sulfonyl)-4-methoxybenzamide 3-(3-acetyl-inden-1-yl)-4-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoate methyl ester 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(phenylsulfonyl)benzamide methyl 5-(3-acetyl-inden-1-yl)-2-((dimethylamino)methyl)-4-methoxybenzoate 3-(3-acetylindoline-1-yl)-N-cyclopropyl-4-methoxybenzamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-((3,5-dichlorophenyl)sulfonyl)-4-methoxybenzamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-benzyl-4-methoxybenzamide 2-((1H-imidazol-1-yl)methyl)-N-benzyl-5-(3-isobutyrylindolazin-1-yl)-4-methoxybenzamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(methylsulfonyl)benzamide N-(3-(3-acetylinden-1-yl)-5-methoxybenzyl)benzenesulfonamide 2-((1H-imidazol-1-yl)methyl)-N-benzyl-5-(3-(cyclopropanecarbonyl)-indene-1-yl)-4-methoxybenzamide 1-(1-(2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one 1-(1-(3,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one 4-(3-acetyl-inden-1-yl)-2,5-dimethoxybenzaldehyde 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one 1-(1-(4-(1-hydroxyethyl)-2,5-dimethoxyphenyl)indene-3-yl)ethyl-1-one 1-(1-(4-(hydroxymethyl)-3,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one 4-(3-acetyl-7-methoxyindene-1-yl)-2,5-dimethoxybenzaldehyde 1-(1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)-7-methoxyindene-3-yl)ethyl-1-one 1-(1-(4-acetyl-2,5-dimethoxyphenyl)azindene-3-yl)ethyl-1-one methyl 4-(3-acetyl-inden-1-yl)-2,6-dimethoxybenzoate 3-(3-acetyl-inden-1-yl)-4-methoxybenzoic acid N-(3-(3-acetylinden-1-yl)-4-methoxyphenyl)-3-methoxybenzenesulfonamide N-(3-(3-acetylinden-1-yl)-4-methoxybenzyl)benzenesulfonamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-(4-(tert-butyl)benzyl)-4-methoxybenzamide N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-cyanobenzenesulfonamide N-(3-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-(methylsulfonyl)benzenesulfonamide N-(3-(3-acetylinden-1-yl)-4-methoxyphenyl)-4-formylbenzenesulfonamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-4-methoxy-N-(3-(trifluoromethyl)benzyl)benzamide 2-((1H-imidazol-1-yl)methyl)-5-(3-acetyl-inden-1-yl)-N-(3-(hydroxymethyl)benzyl)-4-methoxybenzamide 3-(3-acetyl-inden-1-yl)-4-methoxy-N-(pyridin-3-ylsulfonyl)benzamide 3-(3-acetyl-inden-1-yl)-N-((4-bromophenyl)sulfonyl)-4-methoxybenzamide 4-Methoxy-N-(benzenesulfonyl)-3-(3-propionylindoleazine-1-yl)benzamide 4-Methoxy-N-((4-methoxyphenyl)sulfonyl)-3-(3-propionylindoleazine-1-yl)benzamide 3-(3-acetyl-inden-1-yl)-N-((4-bromophenyl)sulfonyl)-5-methoxybenzamide 3-(3-acetyl-inden-1-yl)-N-((4-acetylphenyl)sulfonyl)-5-methoxybenzamide 3-(3-acetyl-inden-1-yl)-5-methoxy-N-((4-methoxyphenyl)sulfonyl)benzamide 3-(3-acetyl-inden-1-yl)-N-(3,5-dichlorophenyl)sulfonyl)-5-methoxybenzamide 3-Methoxy-N-(benzenesulfonyl)-5-(3-propionylindoleazine-1-yl)benzamide N-((4-acetylphenyl)sulfonyl)-3-methoxy-5-(3-propionylindoleazine-1-yl)benzamide 3-(3-acetyl-inden-1-yl)-5-methoxy-N-(benzenesulfonyl)benzamide 3-(3-acetyl-inden-1-yl)-5-methoxy-N-(methylsulfonyl)benzamide N-(3-(3-acetylinden-1-yl)-5-methoxybenzyl)methanesulfonamide N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)benzenesulfonamide 2-((1H-imidazol-1-yl)methyl)-N-benzyl-4-methoxy-5-(3-neovalerylindoleazine-1-yl)benzamide N-(3-(3-isobutylindene-1-yl)-4-methoxyphenyl)benzenesulfonamide N-(4-methoxy-3-(3-neovalerindolazin-1-yl)phenyl)benzenesulfonamide N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)pyridine-2-sulfonamide N-(2-(3-acetyl-inden-1-yl)-4-methoxyphenyl)-4-formylbenzenesulfonamide 3-(3-acetyl-8-ethylinden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide 3-(3-acetyl-8-isopropyl-inden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide 3-(3-acetyl-6-ethylinden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide 3-(3-acetyl-6-isopropyl-inden-1-yl)-4-methoxy-N-(benzenesulfonyl)benzamide 1-(7-(benzyloxy)-1-(2,5-dimethoxyphenyl)azine-3-yl)ethyl-1-one 1-(7-(benzyloxy)-1-(4-(hydroxymethyl)-2,5-dimethoxyphenyl)azind-3-yl)ethyl-1-one 1-(1-(pyridin-2-yl)inden-3-yl)aceto-1-one 1-(1-(3,6-dimethoxypyridin-2-yl)azinden-3-yl)acetoone 1-(1-(4-methoxy-3,5-dimethylphenyl)azinden-3-yl)ethyl-1-one 1-(1-Phenylenindene-3-yl)ethyl-1-one 1-(1-(3-(hydroxymethyl)phenyl)azine-3-yl)ethyl-1-one 1-(1-(2-chlorophenyl)azine-3-yl)ethyl-1-one 1-(1-(3-(trifluoromethyl)phenyl)inden-3-yl)ethyl-1-one 1-(1-(2-methoxyphenyl)azine-3-yl)ethyl-1-one 1-(1-(3-methoxyphenyl)indene-3-yl)ethyl-1-one.

5. A pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound of an indazine compound as described in any one of claims 1-4.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an active ingredient and pharmaceutically acceptable excipients; The active ingredient comprises at least one indazine compound as described in any one of claims 1-4 and / or at least one pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in claim 5.

7. The use of an indazine compound as described in any one of claims 1-4, a pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in claim 5, or a pharmaceutical composition as described in claim 6, in the preparation of a small molecule inhibitor of BRD7 / BRD9 bromodomain protein.

8. The use of an indazine compound as described in any one of claims 1-4, a pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in claim 5, or a pharmaceutical composition as described in claim 6, in the preparation of a medicament for the prevention or treatment of cancer, cell proliferation disorders, inflammatory diseases and autoimmune diseases, sepsis, viral infections, or neurodegenerative diseases.

9. The application according to claim 7 or claim 8, characterized in that, The BRD7 / BRD9 bromodomain receptor inhibitors are used to prepare drugs for the treatment of acute myeloid leukemia, multiple myeloma, melanoma, or prostate cancer.

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