Condensed bicyclic compound as well as preparation method, composition and application thereof

Abstract

The invention relates to a fused bicyclic compound as well as a preparation method, a composition and application thereof. According to the fused bicyclic compound or the pharmaceutically acceptable salt thereof, the fused bicyclic compound has the structural characteristics as shown in the following general formula (I). The fused bicyclic compound can be used as an METTL3 inhibitor and has good activity.

Description

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. 2024113442649, filed on September 25, 2024, entitled "Fused Bicyclic Compounds and Preparation Methods, Compositions and Applications Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of pharmaceutical technology, and in particular to a fused bicyclic compound, its preparation method, composition, and application. Background Technology

[0004] Of all RNA modifications, N 6 -Methyladenine (m 6 A) is the most abundant chemical modification. This modification is distributed in all RNA types, including mRNA, lincRNA, pri-miRNA, and rRNA, and plays a crucial role in physiological function and disease development by regulating gene expression. 6 A is a dynamic and reversible modification, jointly regulated by methyltransferases "writers" (METT3-METTL14, METTL16, and METTL5, etc.), methylation recognition proteins "readers" (YTHDF1-3, YTHDC1, and YTHDC2), and demethylases "erasers" (ALBH5 and FTO). Among these, the METTL3-METTL14 complex is m 6 The key methyltransferase for RNA modification, METTL3, uses S-adenosyl-L-methionine (SAM) as a methyl donor to provide a catalytic site for methylation of substrate RNA, while METTL14 plays the role of recognizing the substrate and stabilizing the complex. The METTL3-METTL14 complex requires the assistance of Wilms' tumor-associated protein (WTAP) to ensure that it locates the correct modification site. METTL3 specifically modifies target RNA, thereby regulating biological processes such as cell cycle, cell proliferation, differentiation, migration, invasion, apoptosis, metabolism, and immune responses.

[0005] Abnormal expression of METTL3 induces the occurrence and development of various types of tumors, including acute myeloid leukemia (AML), breast cancer, liver cancer, malignant glioma, bladder cancer, gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, osteosarcoma, oral squamous cell carcinoma, thyroid cancer, uveal melanoma, ovarian cancer, head and neck squamous cell carcinoma, skin squamous cell carcinoma and nasopharyngeal carcinoma. In AML, the transcription factor CEBPZ (CCAAT enhancer binding protein zeta) stably recruits METTL3 to the promoters of specific active genomes, leading to m 6 A methylation to increase its translation, in which one important target SP1 (Specificity protein 1) regulates c-Myc expression. Therefore, METTL3 can be used as a potential therapeutic target for AML. On the other hand, inhibition of METTL3 makes m 6 A modification is reduced as a whole, leading to the formation of double-stranded RNA, thereby stimulating the cell to produce an endogenous interferon response, while enhancing CD8 + T cell-mediated tumor killing effect, when used in combination with immune checkpoint inhibitors, can enhance the anti-tumor immune effect. In CD4 + Specifically knocking out the Mettl3 gene in T cells, the differentiation of T cells is hindered, thereby inhibiting the occurrence of intestinal inflammation in the intestinal inflammation model induced by T cell adoptive transfer. METTL3 is overexpressed during viral infection outbreaks and regulates the methylation and stability of IFNB mRNA, and when METTL3 is inhibited, the stability and expression of IFNB mRNA are increased, mediating type I interferon expression. In autosomal dominant polycystic kidney disease (ADPKD), METTL3 tends to be highly expressed, and inhibition of METTL3 can slow down the growth of cysts. Therefore, METTL3 plays a key role not only in malignant tumors, but also as a potential target for the treatment of autoimmune diseases, viral infections and other inflammatory diseases, and ADPKD. In summary, the development of METTL3 inhibitors has the potential to treat a variety of diseases.

[0006] There is no specific METTL3 inhibitor approved for marketing at present, and the small molecule METTL3 inhibitor STC-15 of Storm Company, which is the most advanced, entered clinical phase I trial in November 2022, so there is a significant unmet clinical need for the relevant patient population, and it is necessary to provide new compounds that can exert good METTL3 inhibitory activity. SUMMARY

[0007] Based on this, the application provides a fused bicyclic compound which can be used as a METTL3 inhibitor and has good activity, a preparation method of the fused bicyclic compound, a composition containing the fused bicyclic compound, and application of the fused bicyclic compound or the composition in the medical field.

[0008] In a first aspect, the application provides a fused bicyclic compound or a pharmaceutically acceptable salt thereof, the fused bicyclic compound having the structural characteristics shown in the following general formula (I):

[0009]

[0010] wherein,

[0011] X 1 is independently selected from CR A1 , C(R A1 )2, N, NR A2 , O or S;

[0012] X 2 is independently selected from CR A1 , C(R A1 )2, N or NR A2 ;

[0013] X 3 is independently selected from C or N;

[0014] X 4 , X 5 , X 6 and X 7 are each independently selected from N or CR A1 ;

[0015] X 8 and X 9 are each independently selected from C or N;

[0016] wherein,

[0017] R A1 is independently selected from H, halogen, cyano, nitro, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR A1a , -SR A1a , -C(=O)R A1a , -S(=O)R A1a , -S(=O)2R A1a , -C(=O)OR A1a , -OC(=O)R A1a , -NR A1b RA1c -C(=O)NR A1b R A1c -OC(=O)NR A1b R A1c -S(=O)2NR A1b R A1c -NR A1d C(=O)R A1a -NR A1d S(=O)2R A1a wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from H, D, halogen, -OH, cyano, nitro, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, hydroxysubstituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-8 cycloalkyl;

[0018] R A2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C(=O)OR A1a -C(=O)NR A1b R A1c or -S(=O)2R A1a wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently substituted with 1-3 substituents independently selected from H, D, halogen, -OH, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C l-6 haloalkyl, hydroxysubstituted C l-6 alkyl, cyano-substituted C l-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR A2a -SRA2a -C(=O)R A2a -S(=O)R A2a -S(=O)2R A2a -C(=O)OR A2a -OC(=O)R A2a -NR A2b R A2c -C(=O)NR A2b R A2c -OC(=O)NR A2b R A2c -S(=O)2NR A2b R A2c -NR A2d C(=O)R A2a or -NR A2d S(=O)2R A2a ;

[0019] R A1a R A1b R A1c R A2a R A2b and R A2c Each is independently selected from H, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl;

[0020] Or, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A1b and R A1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group, wherein the 4- to 9-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Haloalkyl, optionally, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group, or R A1b and R A1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 6-membered heterocyclic alkyl group;

[0021] Or, R A2b and R A2c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A2b and R A2c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group, wherein the 4- to 9-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Haloalkyl, optionally, R A2b and R A2c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A2b and R A2c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group;

[0022] R A1d and R A2d Each is independently selected from H or C 1-3 alkyl;

[0023] The L mentioned is selected from Or 5 to 6 heteroaryl groups, where L is selected from At that time, it interacts with the carbonyl side The 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, which are independently selected from H, halogens, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0024] in,

[0025] R L1 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 Each cycloalkyl group is optionally substituted with 1 to 3 substituents, said substituents being independently selected from halogens, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6Alkoxy or C 1-6 Halogenated alkoxy groups;

[0026] The B ring is selected from C. 6-10 arylene or 5- to 10-membered heteroarylene, wherein the 5- to 10-membered heteroarylene contains 1 to 5 heteroatoms selected from N, O, and S; wherein the cyclic carbon atom of the 5- to 10-membered heteroarylene may optionally be oxidized and substituted to form a carbonyl group; the C 6-10 The arylene or 5- to 6-membered heteroarylene is independently substituted by 1 to 4 substituents, said substituents being independently selected from H, halogen, -OH, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C l-6 Halogenated alkyl, hydroxylated C l-6 alkyl and cyano substituted C l-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR B1a -SR B1a -C(=O)R B1a -S(=O)R B1a -S(=O)2R B1a -C(=O)OR B1a -OC(=O)R B1a -NR B1b R B1c -C(=O)NR B1b R B1c -OC(=O)NR B1b R B1c -S(=O)2NR B1b R B1c -NR B1d C(=O)R B1a or -NR B1d S(=O)2R B1a The 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O, and S;

[0027] R B1a R B1b and R B1c Each is independently selected from H, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl;

[0028] Or, R B1b and R B1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group, or R B1b and R B1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0029] The R mentioned 1a R 1b R 2a and R 2b Each is independently selected from H, deuterium, halogen, cyano, nitro, hydroxyl, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 4- to 7-membered heterocycloalkyl group are each optionally substituted with 1 to 3 substituents, said substituents being independently selected from H, halogen cyano, nitro, hydroxyl, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy or C 3-6 Cycloalkyl, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S;

[0030] R 1a With R 1b Optionally, it can form carbonyl (=O), thiocarbonyl (=S), or C groups with the atoms it is attached to. 3-6 The cycloalkyl group or heterocyclic group forms a 3- to 6-membered heterocyclic group with another heteroatom selected from O, N, or S, each of which is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0031] R 2aWith R 2b Optionally, it can form carbonyl (=O), thiocarbonyl (=S), or C groups with the atoms it is attached to. 3-6 The cycloalkyl group or heterocyclic group forms a 3- to 6-membered heterocyclic group with another heteroatom selected from O, N, or S, each of which is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0032] The R mentioned 3a and R 3b Each is independently selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl or Wherein, the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0033] Or, R 3a and R 3b Together with the N atom attached thereto, it forms a 3- to 12-membered heterocyclic alkyl group, or R 3a and R 3b The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 3- to 12-membered heterocyclic alkyl group, wherein the 3- to 12-membered heterocyclic alkyl group is optionally substituted with 1 to 3 substituents, the substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0034] The ring C is selected from phenyl, C 3-12 Cycloalkyl or 3 to 12-membered heterocyclic groups, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S; wherein the phenyl, C 3-12The cycloalkyl group and the 3- to 12-membered heterocyclic group are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl or 4- to 7-membered heterocyclic alkyl groups.

[0035] A second aspect of this application provides a pharmaceutical composition comprising the fused bicyclic compound described in the first aspect or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, cocrystal, and

[0036] Pharmaceutically acceptable carrier.

[0037] A third aspect of this application provides the use of the fused bicyclic compound of the first aspect or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect, in the preparation of a medicament for treating and / or preventing diseases associated with or mediated by METTL3 activity.

[0038] A fourth aspect of this application provides the use of the fused bicyclic compound described in the first aspect or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect, and the combination of one or more antitumor drugs in the preparation of a medicament for treating and / or preventing cancers associated with or mediated by METTL3 activity.

[0039] The fused bicyclic compound provided in this application can be used as a METTL3 inhibitor with good activity and can be used to prepare drugs for treating and / or preventing diseases related to or mediated by METTL3 activity. Detailed Implementation

[0040] The following detailed description, in conjunction with specific embodiments, illustrates the fused bicyclic compounds, their preparation methods, compositions, and applications of this application. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0042] As used herein, the terms “and / or,” “or / and,” and “and / or” may include any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all the related listed items.

[0043] In this article, "one or more" refers to any one, two or more of the listed items.

[0044] In this application, terms such as "first aspect," "second aspect," "third aspect," and "fourth aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, terms such as "first," "second," "third," and "fourth" serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0045] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0046] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0047] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0048] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0049] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.

[0050] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0051] The term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon group. Preferably, the alkyl group comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, etc.

[0052] The term "alkoxy" refers to an alkyl group (-O-), wherein the alkyl group is as defined above. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, hexoxy, cyclopropyloxy, cyclohexyloxy, etc. Preferably, the alkoxy group has about 1-6 carbon atoms, more preferably about 1-4 carbon atoms.

[0053] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogen groups as defined herein. Preferably, a haloalkyl group can be a monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. A monohaloalkyl group may have one iodine, bromine, chlorine, or fluorine substituent. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more identical halogen groups or combinations of different halogen groups. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group is an alkyl group in which all hydrogen atoms are substituted with halogen atoms. Preferred haloalkyl groups are trifluoromethyl and difluoromethyl.

[0054] The term "alkenyl" refers to an unsaturated branched or straight-chain group having at least one double bond. Preferably, the alkenyl group comprises 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Alkenyl groups include, but are not limited to, propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, heptenyl, octenyl, etc.

[0055] The term "alkynyl" refers to an unsaturated branched or straight-chain group having at least one triple bond. Preferably, the alkynyl group contains 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Alynyl groups include, but are not limited to, propynyl, 1-butynyl, hexynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, etc.

[0056] The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing a ring of carbon atoms, and can be monocycloalkyl, spirocycloalkyl, or bridged cycloalkyl. Exemplary monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. Exemplary bicycloalkyl groups include bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[1.1.1]pentane, or bicyclo[2.2.2]octyl. Exemplary tricycloalkyl groups include adamantyl. Additionally, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.

[0057] The term "heterocyclic group" refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom, which can be an N atom, O atom, S atom, etc., and wherein the N and S atoms can optionally be oxidized to various oxidation states. In one embodiment, the heterocyclic group is a 4- to 7-membered heterocyclic alkyl group. Examples of heterocyclic groups include dihydrofuranyl, [1,3]dioxolane, 1,4-dioxane, 1,4-dithiane, piperazine, 1,3-dioxolane, imidazoalkyl, imidazolinyl, pyrrolidine, dihydropyran, oxathiolane, dithiopentane, 1,3-dioxane, 1,3-dithiaalkyl, oxathiohexyl, thiomorpholinyl, ethylene oxide, aziridinyl, oxathiobutyl, aziridinyl, tetrahydrofuranyl, pyrrolidine, tetrahydropyranyl, piperidinyl, morpholinyl, piperazine, and aziridinyl. azepinyl, oxo oxapinyl, oxa-nitrogen hybrid oxazepinyl and diaza Radix (diazepinyl).

[0058] The term "spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 double bonds selected from N, O, or S (=O). n heteroatoms.

[0059] The term "cyclic ring" or "cyclic group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds and may be substituted or unsubstituted. Each ring in a cyclic ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10.

[0060] The term "bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected. It may contain zero or more double bonds. Any ring in a fused ring system may contain zero to five groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=O)). n Or O, where n is 0, 1 or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10.

[0061] The terms "aryl" or "aromatic ring" refer to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring attached to the parent structure is the aromatic ring. Understandably, "arylene" refers to a divalent group formed by losing a hydrogen atom from an aryl group.

[0062] The term "heteroaryl" refers to a 5-14 member monocyclic, bicyclic, or tricyclic ring system having 1 to 10 heteroatoms independently selected from N, O, or S, wherein N and S may optionally be oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic. Examples of monocyclic heteroaryl groups include pyridinyl, thiopheneyl, furanyl, pyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. Examples of bicyclic heteroaryl groups include quinolinyl, quinazolinyl, 2,3-diazanaphthyl, quinoxalinyl, zonalinyl, 1,5-diazanaphthyl, pyridopyrimidinyl, pyridopyrazinyl, pteridinyl, indoleyl, isoyindoleyl, indoleyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, isobenzofuranyl, benzothiopheneyl, and benzothiadiyl. Azolyl, azaindolyl, purine, imidazopyridyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, pyidazopyrimidinyl, pyidazopyridyl, pyidazotriazinyl, oxazololopyridyl, isoxazololopyridyl, thiazopyridyl, isothiazololopyridyl, indolyl, benzofuranyl, quinoline, isoquinolinyl, indazole, dihydroindolyl, isoindolyl, indene, benzimidazolyl, and quinolinyl. Understandably, "heteroaryl" refers to a divalent group formed by losing a hydrogen atom from a heteroaryl group.

[0063] The term "substituted" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0064] The terms "optionally" or "optionally" mean that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally (optionally) C substituted with a halogen or cyano group..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0065] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers, diluents, or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0066] The terms "pharmaceutical-grade salt" or "pharmaceutically acceptable salt" refer to salts of the compounds of this invention, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. Salts can be prepared separately during the final isolation and purification of the compound, or by reacting suitable groups with suitable bases or acids. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0067] The term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0068] The term "carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0069] The term "excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0070] The term "prodrug" refers to a compound of the present invention that can be metabolized in vivo to have biological activity. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free amino or carboxyl groups.

[0071] The term "eutectic" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a eutectic form (CCF) through hydrogen bonding or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Eutectic is a multi-component crystal, encompassing both binary eutectics formed between two neutral solids and multi-component eutectics formed between a neutral solid and a salt or solvate.

[0072] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0073] The term "tautomer" refers to functional group isomers that are produced when an atom in a molecule moves rapidly between two positions, such as keto-enol isomers and amide-imine alcohol isomers.

[0074] The term “prevention and / or treatment” includes not only the prevention and / or treatment of disease, but also generally includes preventing the onset of disease, slowing or reversing the progression of disease, preventing or slowing the onset of one or more symptoms associated with disease, reducing and / or alleviating one or more symptoms associated with disease, reducing the severity and / or duration of disease and / or any symptoms associated with it and / or preventing further increase in the severity of disease and / or any symptoms associated with it, preventing, reducing or reversing any physiological damage caused by disease, and any pharmacological effects that are generally beneficial to the patient being treated.

[0075] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0076] In the chemical structure of the compounds described in this invention, the " / " sign indicates that the configuration is not specified; that is, if a chiral isomer exists in the chemical structure, the " / " sign can be any configuration. Or it may contain both configurations.

[0077] In this invention, the single bond connecting the substituents extends through the corresponding ring, indicating that the substituent can be connected to any position on the ring, for example... R is attached to any substituted site on the benzene ring.

[0078] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0079] When the compounds represented by general formula (I) have tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof.

[0080] Some examples of this application provide a fused bicyclic compound or a pharmaceutically acceptable salt thereof, said fused bicyclic compound having the structural features shown in general formula (I):

[0081]

[0082] in,

[0083] X 1 Independently selected from CR A1 C(R) A1 )2, N, NR A2 , O or S;

[0084] X 2 Independently selected from CR A1 C(R) A1 2. N or NR A2 ;

[0085] X 3 Independently selected from C or N;

[0086] X 4 X 5 X 6 and X 7 Each is independently selected from N or CR A1 ;

[0087] X 8 and X 9 Each is independently selected from C or N;

[0088] in,

[0089] R A1 Independently selected from H, halogen, cyano, nitro, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR A1a -SR A1a -C(=O)R A1a -S(=O)R A1a -S(=O)2R A1a -C(=O)OR A1a -OC(=O)R A1a -NR A1b R A1c -C(=O)NR A1b R A1c -OC(=O)NR A1b R A1c -S(=O)2NR A1b R A1c -NR A1d C(=O)R A1a -NR A1d S(=O)2R A1a , wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, D, halogen, -OH, cyano, nitro, -NH2, C1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 cycloalkyl;

[0090] R A2 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C(=O)OR A1a -C(=O)NR A1b R A1c or -S(=O)2R A1a , wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each independently substituted by 1 to 3 substituents, said substituents being independently selected from H, D, halogen, -OH, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C l-6 Halogenated alkyl, hydroxylated C l-6 alkyl and cyano substituted C l-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR A2a -SR A2a -C(=O)R A2a -S(=O)R A2a -S(=O)2R A2a -C(=O)OR A2a -OC(=O)R A2a -NR A2b R A2c -C(=O)NR A2b R A2c -OC(=O)NR A2b R A2c -S(=O)2NR A2b R A2c -NR A2d C(=O)R A2a or -NR A2d S(=O)2R A2a ;

[0091] R A1a R A1b R A1c R A2a R A2b and R A2c Each is independently selected from H, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl;

[0092] Or, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A1b and R A1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group, wherein the 4- to 9-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Haloalkyl, optionally, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group, or R A1b and R A1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 6-membered heterocyclic alkyl group;

[0093] Or, R A2b and R A2c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A2b and R A2c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group, wherein the 4- to 9-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Haloalkyl, optionally, R A2b and R A2c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A2b and R A2c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group;

[0094] R A1d and R A2d Each is independently selected from H or C 1-3 alkyl;

[0095] The L mentioned is selected from Or 5 to 6 heteroaryl groups, where L is selected from At that time, it interacts with the carbonyl side The 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, which are independently selected from H, halogens, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0096] in,

[0097] R L1 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 Each cycloalkyl group is optionally substituted with 1 to 3 substituents, said substituents being independently selected from halogens, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0098] The B ring is selected from C. 6-10 arylene or 5- to 10-membered heteroarylene, wherein the 5- to 10-membered heteroarylene contains 1 to 5 heteroatoms selected from N, O, and S; wherein the cyclic carbon atom of the 5- to 10-membered heteroarylene may optionally be oxidized and substituted to form a carbonyl group; the C 6-10 The arylene or 5- to 6-membered heteroarylene is independently substituted by 1 to 4 substituents, said substituents being independently selected from H, halogen, -OH, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C l-6 Halogenated alkyl, hydroxylated C l-6 alkyl and cyano substituted C l-6 Alkyl, C 3-8Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR B1a -SR B1a -C(=O)R B1a -S(=O)R B1a -S(=O)2R B1a -C(=O)OR B1a -OC(=O)R B1a -NR B1b R B1c -C(=O)NR B1b R B1c -OC(=O)NR B1b R B1c -S(=O)2NR B1b R B1c -NR B1d C(=O)R B1a or -NR B1d S(=O)2R B1a The 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O, and S;

[0099] R B1a R B1b and R B1c Each is independently selected from H, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl;

[0100] Or, R B1b and R B1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group, or R B1b and R B1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0101] The R mentioned 1a R 1b R 2a and R 2bEach is independently selected from H, deuterium, halogen, cyano, nitro, hydroxyl, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 4- to 7-membered heterocycloalkyl group are each optionally substituted with 1 to 3 substituents, said substituents being independently selected from H, halogen cyano, nitro, hydroxyl, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy or C 3-6 Cycloalkyl, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S;

[0102] R 1a With R 1b Optionally, it can form carbonyl (=O), thiocarbonyl (=S), or C groups with the atoms it is attached to. 3-6 The cycloalkyl group or heterocyclic group forms a 3- to 6-membered heterocyclic group with another heteroatom selected from O, N, or S, each of which is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0103] R 2a With R 2b Optionally, it can form carbonyl (=O), thiocarbonyl (=S), or C groups with the atoms it is attached to. 3-6 The cycloalkyl group or heterocyclic group forms a 3- to 6-membered heterocyclic group with another heteroatom selected from O, N, or S, each of which is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0104] The R mentioned 3a and R 3b Each is independently selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl or Wherein, the C 1-6 Alkyl, C 3-8The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0105] Or, R 3a and R 3b Together with the N atom attached thereto, it forms a 3- to 12-membered heterocyclic alkyl group, or R 3a and R 3b The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 3- to 12-membered heterocyclic alkyl group, wherein the 3- to 12-membered heterocyclic alkyl group is optionally substituted with 1 to 3 substituents, the substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0106] The ring C is selected from phenyl, C 3-12 Cycloalkyl or 3 to 12-membered heterocyclic groups, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S; wherein the phenyl, C 3-12 The cycloalkyl group and the 3- to 12-membered heterocyclic group are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl or 4- to 7-membered heterocyclic alkyl groups.

[0107] In some of these examples, Selected from

[0108] m is selected from 0, 1, 2, 3 or 4.

[0109] In some of these examples, R A1 Independently selected from H, halogen, C 1-6 Alkyl, -OR A1a or -NR A1b R A1c R A1a R A1b R A1c Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl, or, R A1b and R A1c Together with the N atom attached thereto, they form 4 to 9-membered heterocyclic alkyl groups, optionally, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group.

[0110] In some of these examples, R A2 Independently selected from H or C 1-6 Alkyl; the C 1-6 Each alkyl group is independently substituted by 1 to 3 substituents, which are independently selected from H, D or halogens.

[0111] In some of these examples, L is selected from... Or a 5-membered heteroaryl group, wherein each of the 5-membered heteroaryl group is optionally substituted by 1-2 substituents, wherein the substituents are independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 alkoxy- or halogen-substituted C 1-4 Alkoxy or C 3-6 The cycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S.

[0112] In some of these examples, L is selected from... The oxazolyl, thiazolyl, thiophene, furanyl, pyrrolyl, pyrazolyl, imidazole, oxadiazole, thiadiazole, or triazoleyl groups are each optionally substituted by 1-2 substituents, the substituents being independently selected from H, F, Cl, Br, I, -OH, cyano, -NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropyl, or cyclobutyl.

[0113] In some of these examples, L is selected from...

[0114] In some of these examples, ring B is selected from 5-5-membered bicyclic heteroaryl, 5-6-membered bicyclic heteroaryl, or 6-6-membered bicyclic heteroaryl, wherein the bicyclic heteroaryl contains 1-5 heteroatoms selected from O, S, and N.

[0115] In some of these examples, ring B is selected from pyridinepyrrolyl, pyridinepyrazolyl, pyridineimidazolyl, pyridinepyrazolyl, pyridineimidazolyl, imidazoimidazolyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, pyridinidinepyrrolyl, pyridinidinepyrazolyl, pyridinidineimidazolyl, pyrimidinidinepyrrolyl, pyrimidinidinepyrazolyl, pyrimidinidineimidazolyl, pyridinidinepyrrolyl, pyridinidinepyrazolyl, pyridinidinepyrrolyl, pyridinidinepyrrolyl, pyridinidinepyrrolyl, pyridinidinepyrrolyl, pyridinidinepyrrolyl, pyridinidineimidazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, benzopyridylpyrazolyl, or pyridinidinepyridazinyl.

[0116] In some of these examples, ring B is selected from benzopyrrole, pyridinopyrrole, benzopyrazolyl, pyridinopyrazolyl, thiazopyrrole, or benzopyridyl.

[0117] In some of these examples, ring B is selected from Ring B passes through *side and R 1a R 1b The carbon atom is substituted and attached;

[0118] in,

[0119] n is selected from 0, 1, 2, 3 or 4;

[0120] R B1 The definition is the same as R A1 Without restriction, R B1 Each independently with R A1 Same or different.

[0121] In some of these examples, R 1a R 1b R 2a and R 2b Each is independently selected from H, deuterium, halogen, cyano, nitro, hydroxyl, -NH2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-4 Alkoxy, C 3-6 The cycloalkyl group and the 4- to 7-membered heterocycloalkyl group are each optionally substituted with 1 to 3 substituents, said substituents being independently selected from H, halogen cyano, nitro, hydroxyl, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S.

[0122] In some of these examples, R 1a R 1b R 2a and R 2b Each of the following groups is independently selected from H, F, Cl, Br, I, cyano, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or aziridine, wherein each of the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or aziridine is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from H, F, Cl, Br, I, -OH, cyano, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or aziridine.

[0123] In some of these examples, R 1a R 1b R 2a and R 2b Each is independently selected from H, F, Cl, Br, I, cyano, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or aziridine.

[0124] In some of these examples, R 1a R 1b R 2a and R 2b Each is independently selected from H.

[0125] In some of these examples, R 3a and R 3b Each is independently selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl or Wherein, the C 1-4 Alkyl, C 3-6The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

[0126] In some of these examples, R 3a and R 3b Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, phenyl, pyridyl, or In this embodiment, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, phenyl, and pyridyl groups are each optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, and C. 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

[0127] In some of these examples, R 3a and R 3b Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, or Wherein, methyl, ethyl, propyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl are each optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from H, F, Cl, Br, I, -OH, =O, cyano, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, or cyclopropyl.

[0128] In some of these examples, R 3a and R 3b Choose either H or C 1-6 alkyl.

[0129] In some of these examples, R 3a and R 3bTogether with the N atom attached thereto, it forms a 4- to 7-membered monoheterocyclic alkyl group, a 4- to 11-membered fused heterocyclic alkyl group, a 5- to 11-membered spirocyclic alkyl group, or a 5- to 12-membered bridged heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from H, halogen, OH, =O, cyano, nitro, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

[0130] In some of these examples, R 3a and R 3b Together with the N atom attached to it, it forms substituted or unsubstituted aziridine, aziridine, piperazine, aziridine-cyclopropyl, aziridine-cyclobutyl, aziridine-cyclopentyl, aziridine-cyclohexyl, aziridine-cyclopentyl, aziridine-cyclopropyl, aziridine-cyclopentyl, aziridine-cyclopentyl, aziridine-cyclopentyl, aziridine-cyclohexyl, aziridine-cyclopropyl, aziridine-cyclobutyl, aziridine-cyclopentyl, aziridine-cyclohexyl, aziridine-aziridine-cyclobutyl, aziridine-aziridine-cyclopentyl, aziridine-aziridine-cyclobutyl, aziridine-aziridine-cyclopentyl, aziridine-aziridine-cyclopentyl, aziridine-cyclopentyl-aziridine, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl Azahexacyclopentyl, azahexacyclopentyl-azahexacyclohexyl, azahexacyclohexyl-azahexacyclobutyl, azahexacyclohexyl-azahexacyclopentyl, azahexacyclohexyl-azahexacyclohexyl, azahexacyclobutylspiroazahexacyclobutyl, azahexacyclobutylspiroazahexacyclopentyl, azahexacyclobutylspiroazahexacyclobutyl, azahexacyclopentylspiroazahexacyclopentyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclopentyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclopentyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl When substituted, it may be further selected by 1-3 groups chosen from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

[0131] In some of these examples, R 3a and R3b Together with the N atom attached thereto, it forms substituted or unsubstituted azirrobutyl, azirropentyl, piperidine, piperazine, azirrobutylspirobutyl, azirrobutylspiropentyl, azirrobutylspirohexyl, azirropentylspirobutyl, azirropentylspiropentyl, azirrohexylspirobutyl, azirrohexylspiropentyl, azirrohexylspirohexyl, when substituted, optionally further substituted by 1-3 substituents selected from H, F, Cl, Br, I, -OH, =O, cyano, -NH2, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, or ethoxy.

[0132] In some of these examples, R 3a and R 3b Together with the N atom it is attached to, it forms either substituted or unsubstituted forms. When substituted, it may optionally be further substituted with 1 to 3 substituents selected from H, F, Cl, Br, I, -OH, =O, cyano, -NH2, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, or ethoxy.

[0133] In some of these examples, the ring C is selected from phenyl, C 3-7 Monocycloalkyl, C 4-11 cycloalkyl, C 5-11 spirocycloalkyl, C 5-12 Bridged cycloalkyl, 4- to 7-membered monoheterocycloalkyl, 4- to 11-membered fused heterocycloalkyl, 5- to 11-membered spiroheterocycloalkyl, 5- to 12-membered bridged heterocycloalkyl, or phenyl, wherein the heterocycloalkyl contains 1 to 3 heteroatoms selected from O, S, and N; the heterocycloalkyl is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

[0134] In some of these examples, the ring C is selected from substituted or unsubstituted phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aziridine, morpholine, piperazine, 1,4-diazaheptanyl, cyclopropylcyclopentyl, cyclopentylcyclobutyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylaziridine, cyclopropylaziridinecyclopentyl, cyclopropylaziridinecyclohexyl, cyclobutylaziridinecyclobutyl, cyclobutylaziridinecyclopentyl, cyclobutylaziridinecyclohexyl, cyclobutylaziridinecyclohexyl, cyclopentylaziridinecyclopentyl, cyclopentylaziridinecyclopentyl, cyclopentylaziridinecyclopentyl, cyclopentylaziridinecyclopentyl Cyclopentyl azidocyclohexyl, cyclohexyl azidocyclobutyl, cyclohexyl azidocyclopentyl, cyclohexyl azidocyclohexyl, azidocyclobutyl azidocyclobutyl, azidocyclobutyl azidocyclopentyl, azidocyclobutyl azidocyclohexyl, azidocyclopentyl azidocyclobutyl, azidocyclopentyl azidocyclopentyl, azidocyclohexyl azidocyclobutyl cyclohexyl azidocyclopentyl, azidocyclohexyl azidocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, azidocyclobutylspirocyclohexyl Cyclobutyl, aziridine spiroaziridine pentyl, aziridine spiroaziridine hexyl, aziridine pentyl spiroaziridine, aziridine pentyl spiroaziridine pentyl, aziridine pentyl spiroaziridine hexyl, aziridine hexyl spiroaziridine butyl, aziridine hexyl spiroaziridine pentyl, aziridine hexyl spiroaziridine hexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, cyclopropyl oxacyclohexyl Cyclobutyl, cyclopropyl oxacyclopentyl, cyclopropyl oxacyclohexyl, cyclobutyl oxacyclobutyl, cyclobutyl oxacyclopentyl, cyclobutyl oxacyclohexyl, cyclopentyl oxacyclopentyl, cyclopentyl oxacyclohexyl, cyclohexyl oxacyclobutyl, cyclohexyl oxacyclopentyl, cyclohexyl oxacyclohexyl, azidocyclobutyl oxacyclobutyl alkyl, aziridine benzoxycyclopentyl, aziridine benzoxycyclohexyl, aziridine benzoxycyclopentyl, aziridine benzoxycyclopentyl, aziridine benzoxycyclohexyl, aziridine benzoxycyclopentyl, aziridine benzoxycyclopentyl, aziridine benzoxycyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl Cyclohexyl, cyclopentylspirocyclohexyl, cyclopentylspirocyclohexyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclohexylspirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexyl, aziridinespirocyclohexylAzacyclopentylspirocyclohexyl, azacyclohexylspirocyclohexyl, azacyclohexylspirocyclohexyl, azacyclohexylspirocyclohexyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl, adamantyl,

[0135] When substituted, it may be further selected by 1-3 groups chosen from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

[0136] In some of these examples, the ring C is selected from substituted or unsubstituted phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylcyclobutyl, or... When substituted, it may optionally be further selected by 1-3 elements selected from H, F, Cl, Br, I, methyl, hydroxyl, =O, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0137] In some of these examples, the compound is selected from one of the following structures:

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146] Other examples of this application provide a pharmaceutical composition comprising the fused bicyclic compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, cocrystal, and a pharmaceutically acceptable carrier thereof.

[0147] Other examples of this application provide the use of fused bicyclic compounds as described above or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, in the preparation of medicaments for treating and / or preventing diseases associated with or mediated by METTL3 activity.

[0148] In some of these examples, the disease is selected from cancer, autoimmune diseases, inflammatory diseases, or autosomal dominant polycystic kidney disease; optionally, the disease is cancer; further optionally, the cancer is selected from acute myeloid leukemia, breast cancer, liver cancer, malignant glioma, bladder cancer, stomach cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, osteosarcoma, oral squamous cell carcinoma, thyroid cancer, uveal melanoma, ovarian cancer, head and neck squamous cell carcinoma, skin squamous cell carcinoma, or nasopharyngeal carcinoma; even more optionally, the cancer is acute myeloid leukemia.

[0149] Other examples of this application provide the use of fused bicyclic compounds as described above or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, and the use of combinations of one or more antitumor drugs in the preparation of medicaments for the treatment and / or prevention of cancers associated with or mediated by METTL3 activity.

[0150] The antitumor drug is selected from one or more of the following: alkylating agents, platinum chelating agents, metabolic antagonists, plant alkaloids, hormone anticancer agents, antibody drugs, VEGFR or EGFR inhibitors, mTOR inhibitors, PI3K kinase inhibitors, B-Raf inhibitors, AKT inhibitors, and immune checkpoint inhibitors. Without limitation, the alkylating agent includes one or more of cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, and dibromomannitol; the platinum chelating agent includes one or more of cisplatin, carboplatin, and oxaliplatin; the metabolic antagonist includes one or more of methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, and pemetrexed; the plant alkaloid includes one or more of vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, and topotecan; the hormonal anticancer agent includes one or more of leuprorelin, goserelin, exemestane, letrozole, anastrozole, and dutasteride; the antibody drug includes... The following are included: one or more of trastuzumab, pertuzumab, rituximab, cetuximab, panitumab, and bevacizumab; the VEGFR or EGFR inhibitors include one or more of sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, and lapatinib; the mTOR inhibitors include everolimus, sirolimus, zotamoxetine, etc., and PI3K kinase inhibitors (one or more of BKM-120, XL-147, and BEZ-235); the B-Raf inhibitors include one or more of vemurafenib and GSK-2118436; the AKT inhibitors include one or more of perifoxetine and MK-2206; and the immune checkpoint inhibitors include one or more of nivolumab and pembrolizumab.

[0151] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0152] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0153] The meanings of the abbreviations in the following examples are shown in Table 1:

[0154] Table 1

[0155]

[0156] The structures of the compounds in the following examples were determined by nuclear magnetic resonance spectroscopy (NMR spectroscopy). 1Confirmation is made by 1H NMR and / or mass spectrometry (MS). NMR shift (δ) is in units of 10⁻⁶. -6 (ppm). NMR measurements were performed using a Buker AVANCE III-400 and Buker AVANCE III-600 NMR spectrometer. Solvents used included deuterated chloroform (d), deuterated dimethyl sulfoxide (d6), and deuterated methanol (d4), with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an Agilent LC / MSD iQ mass liquid chromatography-mass spectrometry system.

[0157] In the following examples, the silica gel plates used for thin-layer chromatography are Shanghai Test Silica Gel Prefabricated Plate GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm to 0.25mm.

[0158] The silica gel column chromatography in the following examples uses 200-300 mesh silica gel as the stationary phase.

[0159] The known starting materials used in the following examples can be synthesized using or according to methods known in the art, or can be purchased from companies such as Bidex Pharmaceutical Technology, Haohong Biomedical Technology, and Sinopharm Group Reagent.

[0160] Unless otherwise specified, the anhydrous solvents used in the following examples were all treated with molecular sieves.

[0161] Unless otherwise specified, the reactions in the following examples can be carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere refers to a reaction flask connected to an approximately 1L volume argon or nitrogen balloon.

[0162] In the following examples, a hydrogen atmosphere refers to a reaction vessel connected to a hydrogen generator at atmospheric pressure.

[0163] Unless otherwise specified, the reaction temperature in the following examples is room temperature, ranging from 20°C to 30°C.

[0164] Preparation of 1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (intermediate A1)

[0165]

[0166] Step a: Preparation of intermediate A1-1

[0167] Methyl 1H-pyrrolo[3,2-c]pyridine-3-carboxylate (150.0 mg, 0.85 mmol) was dissolved in DMF (3 mL), and Cs₂CO₃ (554.8 mg, 1.70 mmol) was added. Iodomethane (63.6 μL, 1.02 mmol) was added under ice bath conditions. After the addition was complete, the mixture was gradually heated to room temperature and stirred for 3 hours at room temperature. The reaction was confirmed by TLC to be complete. The reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to obtain intermediate A1-1 (81.5 mg, yield 50.3%).

[0168] Step b: Preparation of intermediate A1

[0169] Intermediate A1-1 (81.5 mg, 0.43 mmol) was dissolved in a mixed solvent of water (1 mL) and MeOH (3 mL). LiOH·H2O (54.0 mg, 1.29 mmol) was added at room temperature, and the mixture was stirred at 50 °C for 2 hours. TLC analysis confirmed the reaction was complete. The solution was diluted with water, extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. No further purification was required to give a white powdery solid intermediate A1 (45.1 mg, yield 59.8%).

[0170] Preparation of 1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A2) and 2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A3)

[0171]

[0172] Step a: Preparation of intermediates A2-1 and A3-1

[0173] 5-tert-butyl-3-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid (400.0 mg, 1.35 mmol) was dissolved in anhydrous acetonitrile (8 mL), and cesium carbonate (1.3 g, 4.06 mmol) was added at room temperature. The mixture was then cooled to 0 °C, and iodomethane (288.4 mg, 2.03 mmol) was added dropwise under argon protection. The mixture was gradually brought back to room temperature and stirred at room temperature for 2 hours. The reaction was confirmed to be complete by TLC. Dilute with water, extract with ethyl acetate (20 mL * 3), combine organic phases, wash with saturated brine (20 mL * 3), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain crude product, which is then separated and purified by silica gel column chromatography (PE / EA = 8 / 1) to obtain yellow solid intermediate A2-1 (160.0 mg, yield 38%) and light yellow oily liquid intermediate A3-1 (101.8 mg, yield 24%).

[0174] Intermediate A2-1: 1 H NMR(400MHz,Chloroform-d)δ4.57(s,2H),4.35(q,J=7.1Hz,2H),3.79(s,3H),3.68 (d,J=6.0Hz,2H),2.65(t,J=5.7Hz,2H),1.45(s,9H),1.35(t,J=7.1Hz,3H).ESI-MS m / z:309.9[M+H] + .

[0175] Intermediate A3-1: 1 H NMR (400MHz, Chloroform-d) δ4.59 (s, 2H), 4.32 (q, J = 7.1Hz, 2H), 4.11 (s, 3H), 3.67 (d,J=8.5Hz,2H),2.72(t,J=5.9Hz,2H),1.47(s,9H),1.37(t,J=7.1Hz,3H).ESI-MS m / z:310.0[M+H] + .

[0176] Step b: Preparation of intermediates A2-2 and A3-2

[0177] Intermediate A2-1 (160.0 mg, 517.19 μmmol) was dissolved in anhydrous DCM (2 mL), and 4.0 M dioxane hydrochloride solution (2 mL) was added dropwise at room temperature, with stirring for 1 hour. TLC was used to confirm the complete reaction of the starting material. The solution was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give a yellow solid intermediate A2-2 (114.0 mg, 100% yield). ESI-MS m / z: 209.8 [M+H]+ .

[0178] Intermediate A3-2 was prepared using the same method as intermediate A2-2. ESI-MS m / z: 209.9 [M+H] + .

[0179] Step c: Preparation of intermediates A2-3 and A3-3

[0180] Intermediate A2-2 (114.0 mg, 544.81 μmmol) was dissolved in isopropylbenzene (6 mL), and 10% palladium on carbon (60.0 mg) was added at room temperature. The mixture was then heated to 160 °C and refluxed for 24 hours. TLC analysis confirmed complete consumption of the starting material. The solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to give a white solid intermediate A2-3 (76.9 mg, yield 69%).

[0181] 1 H NMR(500MHz,Chloroform-d)δ9.53(d,J=1.2Hz,1H),8.53(d,J=6.0Hz,1H),7.37( dd, J=6.0, 1.2Hz, 1H), 4.55 (q, J=7.1Hz, 2H), 4.17 (s, 3H), 1.49 (t, J=7.1Hz, 3H). ESI-MS m / z:205.8[M+H] + .

[0182] The preparation method of intermediate A3-3 is the same as that of intermediate A2-3.

[0183] 1 H NMR (600MHz, Chloroform-d) δ9.48(d,J=1.4Hz,1H),8.40(d,J=6.2Hz,1H),7.60(dd,J=6.2,1.4Hz,1H),4.57–4.50(m,5H),1.52(t,J=7.1Hz,3H). ESI-MS m / z:205.8[M+H] + .

[0184] Step d: Preparation of intermediate A2

[0185] Intermediate A2-3 (76.9 mg, 374.73 μmmol) was dissolved in THF (2.5 mL), and 1 M sodium hydroxide solution (0.5 mL) was added. The mixture was stirred at room temperature for 3 hours. TLC confirmed complete consumption of the starting material. The solution was neutralized to weakly acidic pH with 4.0 M dioxane hydrochloride solution, and the solution was concentrated under reduced pressure. The resulting white solid, without purification, was used directly in the next reaction. ESI-MS m / z: 177.7 [M+H] + .

[0186] Intermediate A3 was prepared using the same method as intermediate A2. ESI-MS m / z: 177.7 [M+H] + .

[0187] Preparation of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (intermediate A4)

[0188]

[0189] Step a: Preparation of intermediate A4-1

[0190] 3-Bromo-1H-pyrazolo[3,4-d]pyrimidine (300.0 mg, 1.51 mmol) was dissolved in DMF (3 mL), and Cs₂CO₃ (982.3 mg, 3.01 mmol) was added. Iodomethane (112.6 μL, 1.81 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was gradually heated to room temperature and stirred at room temperature for 3 hours. The reaction was confirmed by TLC to be complete. The reaction was quenched with water (100 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give intermediate A4-1 (255.0 mg, yield 97.4%). ESI-MS m / z: 212.6 [M+H] + .

[0191] Step b: Preparation of intermediate A4-2

[0192] Intermediate A4-1 (255.0 mg, 1.20 mmol) was dissolved in a mixed solvent of DMF (3 mL) and MeOH (3 mL). Under an argon atmosphere, TEA (504.4 μL, 3.61 mmol), Pd(PPh3)4 (139.0 mg, 0.36 mmol), and Mo(CO)6 (3175.9 mg, 12.03 mmol) were added sequentially. The mixture was stirred at 80 °C for 3 hours under argon protection. The reaction mixture was checked by TLC to confirm complete reaction. The reaction solution was filtered, the filtrate was diluted with water, extracted with ethyl acetate (30 mL * 3), the organic phases were combined, washed with saturated brine (30 mL * 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to obtain intermediate A4-2 (55.0 mg, yield 23.8%).

[0193] 1 H NMR (400MHz, Chloroform-d) δ9.52(s,1H),9.07(s,1H),4.19(s,3H),4.04(s,3H). ESI-MS m / z:192.9[M+H] + .

[0194] Step c: Preparation of intermediate A4

[0195] Intermediate A4-2 (55.0 mg, 0.29 mmol) was dissolved in a mixed solvent of water (1 mL) and MeOH (3 mL). LiOH·H2O (36.0 mg, 0.86 mmol) was added at room temperature, and the mixture was stirred at 50 °C for 2 hours. The solution was diluted with water, extracted with ethyl acetate (10 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. No further purification was required to give a white powdery solid A4 (37.8 mg, yield 74.1%).

[0196] 1 H NMR (400MHz, Methanol-d4) δ9.51(s,1H),9.06(s,1H),4.20(s,3H). ESI-MS m / z:178.7[M+H] + .

[0197] Preparation of 7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (intermediate A5)

[0198]

[0199] Following the preparation method of intermediate A1, methyl 7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid was used instead of methyl 1H-pyrrolo[3,2-c]pyridine-3-carboxylate to obtain intermediate A5, a white solid. ESI-MS m / z: 177.8 [M+H] + .

[0200] 5-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A6)

[0201]

[0202] Following the preparation method of intermediate A1, replacing intermediate A1-1 with intermediate A2-1 yields white solid intermediate A6. ESI-MS m / z: 281.9 [M+H] + .

[0203] 1-Methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (intermediate A7)

[0204]

[0205] Following the preparation method of intermediate A2, replacing 5-tert-butyl-3-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid with 5-(tert-butyl)-3-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid yields a white solid intermediate A7. ESI-MS m / z: 177.8 [M+H] + .

[0206] Imidazo[1,5-a]pyrazine-1-carboxylic acid (intermediate A8)

[0207]

[0208] Following the preparation method of intermediate A2, replacing intermediate A2-3 with ethyl imidazo[1,5-a]pyrazine-1-carboxylate yields white solid intermediate A8. ESI-MS m / z: 185.7 [M+Na] + .

[0209] 3-Methylimidazo[1,5-a]pyrazine-1-carboxylic acid (intermediate A9)

[0210]

[0211] Step a: Synthesis of intermediate A9-1

[0212] At room temperature, 2-aminomethylpyrazine (5.00 g, 45.82 mmol) and triethylamine (6.95 g, 68.72 mmol) were added to a single-necked flask and dissolved in DCM (100 mL). The mixture was cooled to 0 °C in an ice bath, and acetyl chloride (5.39 g, 68.72 mmol) was slowly added dropwise to the solution. The reaction was allowed to proceed at room temperature for 2 hours. TLC showed no starting material remaining. The mixture was then cooled to 0 °C in an ice bath, quenched with methanol (100 mL), and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a colorless oily liquid (2.7 g, yield 39.6%). 1 H NMR (600MHz, Chloroform-d) δ 8.59 (d, J = 1.4 Hz, 1H), 8.49 (dt, J = 4.8, 2.5 Hz, 2H), 6.57 (s, 1H), 4.60 (d, J = 5.3 Hz, 2H), 2.07 (s, 3H). ESI-MS m / z:152.0[M+H] + .

[0213] Step b: Synthesis of intermediate A9-2

[0214] Compound A9-1 (2.74 g, 18.15 mmol) was added to a single-necked flask at room temperature, dissolved in phosphorus oxychloride (10 mL), and DMF (1 mL) was added. The mixture was heated to 55 °C and stirred for 3 hours. TLC showed no starting material remaining. The reaction mixture was placed in an ice bath, and ammonia-methanol (500 mL) was added to quench the reaction mixture. The mixture was then concentrated under reduced pressure. The crude product was purified by column chromatography to give a white solid (889 mg, yield 36.8%).

[0215] 1 H NMR (400MHz, Chloroform-d) δ8.95–8.87(m,1H),7.72(d,J=1.0Hz,1H),7.57(dt,J=5.2,1.3Hz,1H),7.52(d,J=5.1Hz,1H),2.68(s,3H). ESI-MS m / z:133.8[M+H] + .

[0216] Step c: Synthesis of intermediate A9-3

[0217] Compound A9-2 (889.0 mg, 6.68 mmol) was added to a single-necked flask at room temperature and dissolved in DMF (30 mL). N-iodosuccinimide (1.65 g, 7.34 mmol) was added to the solution, and the reaction was carried out at room temperature for 2 hours. TLC showed no starting material remaining. The reaction solution was quenched with saturated sodium thiosulfate solution (50 mL), extracted with EA (2 × 50 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give a yellow solid (1.0 g, yield 57.8%).

[0218] 1 H NMR (400MHz, Chloroform-d) δ 8.74 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.53 (dd, J = 5.0, 1.5 Hz, 1H), 2.68 (s, 3H). ESI-MS m / z:259.7[M+H] + .

[0219] Step d: Synthesis of intermediate A9-4

[0220] At room temperature, compound A9-3 (1.0 g, 3.86 mmol) and molybdenum hexacarbonyl (10.19 g, 38.60 mmol) were added to a sealed tube and dissolved in DMF:MeOH (1:1, v / v, 100 mL). Triethylamine (1.2 g, 11.58 mmol) was added, and the mixture was purged three times with argon. Tetra(triphenylphosphine)palladium (1.34 g, 1.16 mmol) was added, and the mixture was heated to 80 °C for 12 hours. TLC showed no starting material remaining. Saturated ammonium chloride solution (200 mL) was added to the reaction solution, and the mixture was extracted with EA (2 × 200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to give a white solid (250.0 mg, yield 33.9%).

[0221] 1 H NMR (400MHz, Chloroform-d) δ9.57 (s, 1H), 7.81 (d, J = 5.0 Hz, 1H), 7.71 (dd, J = 5.0, 1.7 Hz, 1H), 4.02 (s, 3H), 2.73 (s, 3H). ESI-MS m / z:191.8[M+H] + .

[0222] Step e: Synthesis of intermediate A9

[0223] Following the preparation method of intermediate A1, white solid intermediate A9 was obtained from intermediate A9-4.

[0224] Preparation of 1-ethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A10) & 2-ethyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A11)

[0225]

[0226] Following the preparation methods of intermediates A2 and A3, replacing iodomethane with iodoethane yields white solid intermediates A10 and A11.

[0227] A10: ESI-MS m / z: 191.9 [M+H] + A11: ESI-MS m / z: 191.9 [M+H] + .

[0228] Preparation of 1-isopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A12) & 2-isopropyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A13)

[0229]

[0230] Following the preparation methods of intermediates A2 and A3, replacing iodomethane with iodoisopropane yields white solid intermediates A12 and A13.

[0231] A12: ESI-MS m / z: 205.8 [M+H] + A13: ESI-MS m / z: 205.8 [M+H] + .

[0232] Preparation of 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A14)

[0233]

[0234] Following the preparation method of intermediate A2, replacing iodomethane with 2,2,2-trifluoroethyltrifluoromethane sulfonate yields intermediate A14, a white solid. ESI-MS m / z: 245.8 [M+H] + .

[0235] Preparation of 1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A15)

[0236]

[0237] Following the preparation method of intermediate A2, replacing iodomethane with 1,1-difluoro-2-iodoethane yields intermediate A15, a white solid.

[0238] Preparation of 1-(methyl-d3)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A16)

[0239]

[0240] Following the preparation method of intermediate A2, replacing iodomethane with deuterated iodomethane yields intermediate A16, a white solid. ESI-MS m / z: 180.8 [M+H] + .

[0241] 1,7-Dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A17)

[0242]

[0243] Step a: Synthesis of intermediate A17-1

[0244] N-Boc-3-methyl-piperidin-4-one (500.0 mg, 2.34 mmol) was placed in a Schlenk flask, purged with argon three times, and anhydrous THF (10 mL) was added. The reaction mixture was placed at -78 °C, and LDA (2.0 M in THF, 2.81 mmol) was added dropwise. The mixture was stirred for 1 hour, followed by the addition of diethyl oxalate (342.6 mg, 2.34 mmol), and the temperature was slowly raised to room temperature. The mixture was stirred for 2 hours. TLC was used to monitor complete consumption of the starting material. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a yellow oily racemic mixture (373.0 mg, 51% yield). ESI-MS m / z: 311.9 [MH] - .

[0245] Step b: Synthesis of intermediate A17-2

[0246] Intermediate A17-1 (373.0 mg, 1.19 mmol) was dissolved in acetic acid (3 mL), and hydrazine hydrate (178.8 mg, 3.57 mmol) was added. The mixture was stirred at room temperature for 2 hours. TLC analysis confirmed complete consumption of the starting material. The solution was neutralized with saturated sodium bicarbonate, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a pale yellow oily liquid (373.0 mg, 100% yield). ESI-MS m / z: 309.9 [M+H] + .

[0247] Step cf: Synthesis of intermediate A17

[0248] Following the preparation method of intermediate A2, replacing 5-tert-butyl-3-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid with intermediate A17-2 yields intermediate A17 as a white solid. ESI-MS m / z: 191.8 [M+H] + .

[0249] 1,6-Dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A18)

[0250]

[0251] Following the synthetic method for intermediate A17, white solid intermediate A18 was obtained from 1-tert-butoxycarbonyl-2-methylpiperidinone. ESI-MS m / z: 191.9 [M+H] + .

[0252] 7-Bromo-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A19)

[0253]

[0254] Step a: Synthesis of intermediate A19-1

[0255] Intermediate A2-3 (5.0 g, 24.36 mmol) was dissolved in DMF (5 mL), and N-bromosuccinimide (8.7 g, 48.73 mmol) was added. The mixture was heated to 80 °C and stirred overnight. TLC was used to confirm the reaction was complete. The reaction solution was diluted with water, extracted with EA, washed with saturated sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography was used to purify the crude product into a yellow solid, intermediate A19-1 (4.8 g, 69% yield). ESI-MS m / z: 283.9 [M+H] + .

[0256] Step b: Synthesis of intermediate A19

[0257] Following the synthesis method of intermediate A2, a white solid intermediate A19 was prepared from intermediate A19-1. ESI-MS m / z: 256.0 [M+H] + .

[0258] 7-((2,4-dimethoxybenzyl)(methyl)amino)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate A20)

[0259]

[0260] Step a: Synthesis of intermediate A20-1

[0261] Intermediate A19-1 (500.0 mg, 1.76 mmol), 2,4-dimethoxy-N-methylbenzylamine (478.4 mg, 2.64 mmol), tris(dibenzylacetone)palladium (161.2 mg, 0.18 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (167.8 mg, 0.36 mmol), and cesium carbonate (1.4 g, 4.40 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The mixture was purged three times with argon gas, heated to 100 °C, and stirred overnight. TLC was used to confirm the complete reaction of the starting material. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to give intermediate A20-1 (237.0 mg, 35% yield), a yellow oily liquid. ESI-MS m / z: 384.9 [M+H] + .

[0262] Step b: Synthesis of intermediate A20

[0263] Following the synthesis method of intermediate A2, a white solid intermediate A20 was prepared from intermediate A20-1. ESI-MS m / z: 356.8 [M+H] + .

[0264] 1-Methyl-7-(methyl-d3)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A21)

[0265]

[0266] Step a: Synthesis of intermediate A21-1

[0267] N-tert-Butoxycarbonyl-4-piperidinone (10.0 g, 50.19 mmol) was dissolved in anhydrous THF (100 mL), cooled to -78 °C, and 2.0 M diisopropylaminolithium solution (37.5 mL, 75.28 mmol) was slowly added dropwise. After stirring for 30 minutes, deuterated iodomethane (8.0 g, 55.21 mmol) was added dropwise, and stirring was continued for 2 hours. The reaction of the starting material was confirmed by TLC to be complete. The reaction was quenched with saturated ammonium chloride solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a yellow oily liquid (5.1 g, yield 47%).

[0268] Step bg: Synthesis of intermediate A21

[0269] Following the synthetic method for intermediate A17, N-Boc-3-methyl-piperidin-4-one was replaced with intermediate A21-1 to obtain a white solid intermediate A21. ESI-MS m / z: 194.9 [M+H] + .

[0270] Preparation of (2-(diethoxymethyl)-1H-indol-6-yl)methylamine (intermediate B1)

[0271]

[0272] Step a: Preparation of intermediate B1-1

[0273] 3-Amino-4-iodobenzonitrile (1.0 g, 4.46 mmol) was dissolved in THF (10 mL). Then, 3,3-diethoxyprop-1-yne (767.9 μL, 5.36 mmol), PdCl2(PPh3)2 (31.3 mg, 0.04 mmol), PPh3 (23.4 mg, 0.09 mmol), CuI (17.0 mg, 0.09 mmol), and TEA (10 mL) were added sequentially at room temperature. Argon gas was purged three times, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was checked by TLC to ensure complete reaction. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL * 3). The filtrate was collected and concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain intermediate B1-1 (1.0 g, yield 91.8%).

[0274] 1 H NMR(600MHz,Chloroform-d)δ7.36–7.34(m,1H),6.94–6.89(m,2H),5.52(s,1H),4.43( s, 2H), 3.80 (dq, J = 9.5, 7.1Hz, 2H), 3.66 (dq, J = 9.5, 7.1Hz, 2H), 1.27 (t, J = 7.1Hz, 6H).

[0275] Step b: Preparation of intermediate B1-2

[0276] Intermediate B1-1 (1.0 g, 4.09 mmol) was dissolved in NMP (10 mL), and potassium tert-butoxide (919.2 mg, 8.19 mmol) was added under ice bath conditions. After the addition was complete, the mixture was heated to room temperature and stirred for 18 hours. The reaction of the starting material was confirmed by TLC to be complete. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain intermediate B1-2 (412.4 mg, yield 41.2%).

[0277] 1 H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.71(s,1H),7.64(d,J=8.3Hz,1H),7.33(d ,J=8.2Hz,1H),6.59(s,1H),5.78(s,1H),3.65(q,J=7.9Hz,4H),1.27(t,J=7.2Hz,6H).

[0278] Step c: Preparation of intermediate B1

[0279] Intermediate B1-2 (300.0 mg, 1.22 mmol) was dissolved in ethanol (5 mL). At room temperature, 7.0 M ammonia-methanol solution (3.0 mL) and Raney nickel (432.7 mg, 6.0 mmol) were added sequentially. After the addition was complete, the mixture was purged with argon three times, then purged with hydrogen, and stirred at 50 °C for 5 hours in a hydrogen atmosphere. TLC was used to confirm the completeness of the reaction. The reaction mixture was filtered, and the filter cake was washed with methanol (15 mL x 2). The filtrate was collected and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (DCM / MeOH·NH3 = 50 / 1) to obtain intermediate B1 (200.0 mg, yield 67.8%).

[0280] 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=8.1Hz,1H),7.30(s,1H),6.94(dd,J=8.1,1.5Hz,1H),6.34(d,J=2 .0Hz,1H),5.67(s,1H),3.76(s,2H),3.62–3.49(m,4H),2.09–1.68(brs,2H),1.17(t,J=7.0Hz,6H).

[0281] (2-(diethoxymethyl)-1-methyl-1H-indol-6-yl)methylamine (intermediate B2)

[0282]

[0283] Step a: Synthesis of intermediate B2-1

[0284] Intermediate B2-1 (600.0 mg, 2.46 mmol) was dissolved in anhydrous DMF. Sodium hydride (245.6 mg, 6.14 mmol) was added under ice bath conditions. After stirring at room temperature for 10 minutes, iodomethane (697.2 mg, 4.91 mmol) was added dropwise under ice bath conditions. The mixture was then stirred at room temperature for 1 hour. TLC was used to monitor complete consumption of the starting material. The solution was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a pale yellow oily liquid (609.3 mg, 96% yield).

[0285] 1 H NMR(400MHz,Chloroform-d)δ7.69–7.58(m,2H),7.31(dd,J=8.2,1.4Hz,1H),6.65( d,J=1.0Hz,1H),5.67(s,1H),3.84(s,3H),3.72–3.54(m,4H),1.24(t,J=7.1Hz,6H). ESI-MS m / z:258.9[M+H] + .

[0286] Step b: Synthesis of intermediate B2

[0287] Following the preparation method of intermediate B1, intermediate B2-1 is used to replace B1-2 to obtain intermediate B2, which is a yellow solid.

[0288] 1 H NMR(400MHz,Chloroform-d)δ7.54(d,J=8.0Hz,1H),7.28(d,J=1.5Hz,1H),7.03(dd,J=8.1,1.4Hz,1H),6.56(d ,J=2.9Hz,1H),5.83–5.53(m,1H),3.99(s,2H),3.81(d,J=1.8Hz,3H),3.68–3.54(m,4H),1.23(t,J=7.1Hz,6H). ESI-MS m / z:262.8[M+H] + .

[0289] (2-(diethoxymethyl)-1H-indol-6-yl)methylamine (intermediate B3)

[0290]

[0291] Following the preparation method of intermediate B1, replacing 3-amino-4-iodobenzonitrile with 5-amino-4-bromo-2-fluorobenzonitrile yields intermediate B3, a yellow oily liquid. ESI-MS m / z: 266.8 [M+H] + .

[0292] (7-(diethoxymethyl)-1-methoxyisoquinoline-3-yl)methylamine (intermediate B4)

[0293]

[0294] Step a: Synthesis of intermediate B4-1

[0295] 6-Bromo-1,3-dichloroisoquinoline (2.0 g, 7.22 mmol) was dissolved in methanol (25 mL), and sodium methoxide (780.3 mg, 14.44 mmol) was added. The mixture was stirred at 80 °C for 16 hours. TLC analysis showed the reaction was complete. The solution was diluted with water, filtered, and the filter cake was washed with ethyl acetate to give a pale yellow solid (1.7 g, 86% yield). ESI-MS m / z: 272.1 [M+H] + .

[0296] Step b: Synthesis of intermediate B4-2

[0297] Intermediate B4-1 (1.7 g, 6.24 mmol) was dissolved in anhydrous THF (20 mL), cooled to -78 °C, and 2.5 Mn-BuLi (3.8 mL, 9.36 mmol) was slowly added dropwise. After stirring for 30 minutes, N,N-dimethylformamide (912.0 mg, 12.48 mmol) was added, and stirring continued for 3 hours. TLC analysis confirmed the reaction was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily liquid (750.0 mg, yield 54%). ESI-MS m / z: 221.9 [M+H] + .

[0298] Step c: Synthesis of intermediate B4-3

[0299] Intermediate B4-2 (750.0 mg, 3.38 mmol) was dissolved in ethanol (10 mL), and triethyl orthoformate (501.5 mg, 3.38 mmol) and TsOH (582.7 mg, 3.38 mmol) were added. The mixture was heated to 80 °C and refluxed with stirring overnight. TLC analysis confirmed complete reaction of the starting material. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain a yellow oily liquid (840 mg, yield 84%). ESI-MS m / z: 295.9 [M+H] + .

[0300] Step d: Synthesis of intermediate B4-4

[0301] Intermediate B4-3 (840 mg, 2.84 mmol) and zinc cyanide (500.0 mg, 4.26 mmol) were mixed in 15 mL of anhydrous DMF. After purging with argon for 5 minutes, 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (207.8 mg, 0.28 mmol) was added. The mixture was heated to 100 °C under an argon atmosphere and stirred overnight. TLC was used to confirm complete reaction of the starting material. The mixture was diluted with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give a yellow solid (420 mg, 52% yield). ESI-MS m / z: 287.1 [M+H] + .

[0302] Step e: Synthesis of intermediate B4

[0303] Following the preparation method of intermediate B1, intermediate B1-2 was replaced with intermediate B4-4 to prepare a yellow oily liquid intermediate B4. ESI-MS m / z: 291.1 [M+H] + .

[0304] (7-(diethoxymethyl)-1-methoxyisoquinoline-3-yl)methylamine (intermediate B5)

[0305]

[0306] Step a: Synthesis of intermediate B5-1

[0307] Following the preparation method of intermediate B4-2, intermediate B4-1 was prepared by replacing it with 6-bromo-1,3-dichloroisoquinoline, yielding a yellow oily liquid intermediate B5-1. ESI-MS m / z: 225.8 [M+H] + .

[0308] Step b: Synthesis of intermediate B5-2

[0309] Following the preparation method of intermediate B4-3, intermediate B4-2 was replaced with intermediate B5-1 to prepare a yellow oily liquid intermediate B5-2. ESI-MS m / z: 299.8 [M+H] + .

[0310] Step c: Synthesis of intermediate B5-3

[0311] Intermediate B5-2 (535.0 mg, 1.78 mmol), potassium methyltrifluoroborate (326.0 mg, 2.67 mmol), potassium carbonate (492.6 mg, 3.56 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (130.4 mg, 0.18 mmol) were dissolved in a 1,4-dioxane / water mixture (10 mL, v / v = 4 / 1). The mixture was purged three times with argon gas and stirred at 100 °C for 4 hours. The reaction mixture was analyzed by TLC to confirm complete reaction. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain a yellow oily liquid intermediate B5-3 (315 mg, yield 63%). ESI-MS m / z: 280.2 [M+H] + .

[0312] Step d: Synthesis of intermediate B5-4

[0313] Following the preparation method of intermediate B4-4, intermediate B4-3 was replaced with intermediate B5-3 to prepare a yellow solid intermediate B5-4. ESI-MS m / z: 270.8 [M+H] + .

[0314] Step e: Synthesis of intermediate B5

[0315] Following the preparation method of intermediate B4, intermediate B4-4 was replaced with intermediate B5-4 to prepare a yellow oily liquid intermediate B5. ESI-MS m / z: 274.9 [M+H] + .

[0316] Example 1: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)pyrazolo[1,5-a]pyrazine-3-carboxamide (Compound 1)

[0317]

[0318] Step a: Synthesis of intermediate 1-1

[0319] Pyrrolo[1,2-a]pyrazine-8-carboxylic acid (44.0 mg, 0.18 mmol) was dissolved in DMF (2 mL), and DIPEA (92.7 μL, 0.53 mmol) and HATU (80.9 mg, 0.21 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. Subsequently, the DMF solution of intermediate B1 was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The reaction of the starting material was confirmed by TLC to be complete. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1-1 (47.5 mg, yield 68.1%), which was used directly in the next step of the reaction.

[0320] Step b: Synthesis of intermediates 1-2

[0321] Intermediate 1-1 (47.5 mg, 0.12 mmol) was dissolved in a mixed solvent of THF (5 mL) and water (0.5 mL), and glacial acetic acid (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. TLC analysis showed that the reaction proceeded completely. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added. A large amount of solid precipitated out. The solid was filtered, and the filter cake was washed with water (5 mL x 3) and diethyl ether (5 mL x 3). The filter cake was collected and dried under vacuum to give intermediate 1-2 (37.9 mg, yield 98.3%). ESI-MS m / z: 320.0 [M+H] + .

[0322] Step c: Synthesis of Compound 1

[0323] Intermediates 1-2 (37.9 mg, 0.12 mmol) and cyclobutylmethylamine (22.8 μL, 0.24 mmol) were dissolved in DCE (2 mL) and stirred at 65 °C for 1 hour. The reaction was cooled to room temperature, and then STAB (75.5 mg, 0.36 mmol) was added. After the addition was complete, the temperature was raised to 65 °C and stirred for another 2 hours. The reaction was confirmed by TLC to be complete. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (DCM / MeOH·NH3 = 8 / 1) to give compound 1 (24.1 mg, yield 52.3%).

[0324] 1H NMR(400MHz,Chloroform-d)δ9.73(d,J=1.4Hz,1H),8.81(s,1H),8.33(dd,J=4.7,1.5Hz,1H),8.17(s ,1H),7.98(d,J=4.7Hz,1H),7.46(d,J=8.0Hz,1H),7.27(s,1H),7.03(dd,J=8.1,1.5Hz,1H),6.66(t,J =5.5Hz,1H),6.40–6.18(m,1H),4.69(d,J=5.5Hz,2H),3.90(s,2H),2.64(d,J=7.3Hz,2H),2.46(p,J=7 .6Hz,1H),2.03(qdd,J=7.5,3.9,1.6Hz,2H),1.95–1.83(m,1H),1.83–1.76(m,2H),1.69–1.57(m,2H). ESI-MS m / z:388.9[M+H] + .

[0325] Example 2: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide (Compound 2)

[0326]

[0327] Step a: Synthesis of intermediate 2-1

[0328] Intermediate A1 (45.1 mg, 0.26 mmol) was dissolved in DMF (2 mL), and DIPEA (111.6 μL, 0.64 mmol) and HATU (97.5 mg, 0.26 mmol) were added sequentially. The mixture was stirred at room temperature for 30 minutes. Then, the DMF solution of B1 was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. TLC was used to determine if the reaction was complete. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 2-1 (50.0 mg, yield 67.7%), which was used directly in the next reaction step.

[0329] Step b: Synthesis of intermediate 2-2

[0330] Intermediate 2-1 (50.0 mg, 0.12 mmol) was dissolved in a mixed solvent of THF (5 mL) and water (0.5 mL), and glacial acetic acid (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. TLC analysis confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by pre-TLC (DCM / MeOH·NH3 = 15 / 1) to give intermediate 2-2 (38.6 mg, yield 94.4%). ESI-MS m / z: 332.9 [M+H] + .

[0331] Step c: Synthesis of compound 2

[0332] Intermediate 2-2 (38.6 mg, 0.12 mmol) and cyclobutylmethylamine (19.8 μL, 0.23 mmol) were dissolved in DCE (2 mL) and stirred at 65 °C for 1 hour. The reaction was cooled to room temperature, and then STAB (73.9 mg, 0.35 mmol) was added. After the addition was complete, the temperature was raised to 65 °C and stirred for another 2 hours. The reaction was confirmed by TLC to be complete. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (DCM / MeOH·NH3 = 10 / 1) to give compound 2 (17.6 mg, yield 37.7%).

[0333] 1 H NMR(400MHz,Chloroform-d)δ9.30(d,J=1.1Hz,1H),9.28–9.22(m,1H),8.31(d,J=5.8Hz,1H),7.50 (s,1H),7.45(d,J=8.1Hz,1H),7.26(s,1H),7.14(dd,J=5.9,1.1Hz,1H),7.03(dd,J=8.1,1.5Hz,1H ),6.66(t,J=5.5Hz,1H),6.26(d,J=1.7Hz,1H),4.66(d,J=5.5Hz,2H),3.87(s,2H),3.65(s,3H),2. 62(d,J=7.3Hz,2H), 2.44(p,J=7.7Hz,1H), 2.06–1.96(m,3H), 1.92–1.73(m,2H), 1.69–1.54(m,2H). ESI-MS m / z:402.0[M+H] + .

[0334] Example 3: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 3)

[0335]

[0336] Step a: Synthesis of intermediate 3-1

[0337] Intermediate A2 (32.7 mg, 0.18 mmol) was dissolved in DMF (2 mL), followed by the addition of DIPEA (59.7 μL, 0.46 mmol) and HATU (70.2 mg, 0.18 mmol) at room temperature for 30 minutes. Then, the DMF solution of B1 was slowly added dropwise to the reaction mixture, and the reaction was allowed to proceed for 6 hours at room temperature. TLC was used to confirm the complete reaction of the starting material. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 3-1 (21.7 mg, yield 40.4%), which was used directly in the next step.

[0338] Step b: Synthesis of intermediate 3-2

[0339] Intermediate 3-1 (21.8 mg, 0.065 mmol) was dissolved in a mixed solvent of THF (5 mL) and water (0.5 mL), and glacial acetic acid (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was checked by TLC to confirm complete reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by pre-TLC (DCM / MeOH·NH3 = 10 / 1) to obtain intermediate 3-2 (14.2 mg, yield 82.4%).

[0340] 1 H NMR(400MHz, Methanol-d4)δ9.77(s,1H),9.47(d,J=1.3Hz,1H),8.40(d,J=6.2Hz,1H),7.72–7.6 5(m,2H),7.50(s,1H),7.33–7.26(m,1H),7.19(dd,J=8.3,1.5Hz,1H),4.74(s,2H),4.16(s,3H). ESI-MS m / z:333.9[M+H] + .

[0341] Step c: Synthesis of compound 3

[0342] Intermediate 3-2 (14.2 mg, 0.042 mmol) and cyclobutylmethylamine (8.0 μL, 0.084 mmol) were dissolved in DCE (2 mL) and stirred at 65 °C for 1 hour. The reaction was cooled to room temperature, and then STAB (26.8 mg, 0.126 mmol) was added. After the addition was complete, the mixture was heated to 65 °C and stirred for another 2 hours. The reaction was confirmed by TLC to be complete. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (DCM / MeOH·NH3 = 10 / 1) to give compound 3 (7.0 mg, yield 40.8%).

[0343] 1 H NMR(400MHz,Chloroform-d)δ9.72(d,J=1.3Hz,1H),8.74(s,1H),8.49(d,J=6.0Hz,1H),7.52(d,J =8.0Hz,1H),7.38(s,1H),7.31(d,J=1.3Hz,1H),7.29(d,J=1.2Hz,1H),7.11(dd,J=8.1,1.5Hz,1H) ,6.32(d,J=1.8Hz,1H),4.77(d,J=5.7Hz,2H),4.05(s,3H),3.94(s,2H),2.65(d,J=7.2Hz,2H),2.4 7(p,J=7.6Hz,1H),2.22(t,J=7.6Hz,1H),2.08–1.98(m,2H),1.93–1.81(m,2H),1.71–1.56(m,2H). ESI-MS m / z:403.0[M+H] + .

[0344] Example 4: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (Compound 4)

[0345]

[0346] Step a: Synthesis of intermediate 4-1

[0347] Intermediate A4 (37.8 mg, 0.21 mmol) was dissolved in DMF (2 mL), followed by the addition of DIPEA (93.8 μL, 0.53 mmol) and HATU (63.7 mg, 0.18 mmol) at room temperature for 30 minutes. Then, the DMF solution of B1 was slowly added dropwise to the reaction mixture, and the reaction was allowed to proceed for 6 hours at room temperature. TLC was used to confirm the complete reaction of the starting material. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 4-1 (23.7 mg, yield 38.1%), which was used directly in the next step.

[0348] Step b: Synthesis of intermediate 4-2

[0349] Intermediate 4-1 (23.7 mg, 0.071 mmol) was dissolved in a mixed solvent of THF (5 mL) and water (0.5 mL), and glacial acetic acid (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was checked by TLC to confirm complete reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by pre-TLC (DCM / MeOH·NH3 = 10 / 1) to obtain intermediate 4-2 (14.7 mg, yield 82.4%).

[0350] 1 H NMR (400MHz, Methanol-d4) δ10.09 (s, 1H), 9.77 (s, 1H), 7.69 (d, J = 8.3Hz, 1H), 7.45 (s, 1H) ),7.37–7.33(m,1H),7.29(s,1H),7.13(dd,J=8.4,1.5Hz,1H),4.64(s,2H),3.63(s,3H). ESI-MS m / z:334.9[M+H] + .

[0351] Step c: Synthesis of compound 4

[0352] Intermediate 4-2 (14.7 mg, 0.043 mmol) and cyclobutylmethylamine (8.0 μL, 0.085 mmol) were dissolved in DCE (2 mL) and stirred at 65 °C for 1 hour. The reaction was cooled to room temperature, and then STAB (27.6 mg, 0.136 mmol) was added. After the addition was complete, the mixture was heated to 65 °C and stirred for another 2 hours. The reaction was confirmed by TLC to be complete. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-TLC (DCM / MeOH·NH3 = 8 / 1) to give compound 4 (8.0 mg, yield 45.1%).

[0353] 1 H NMR(400MHz,Chloroform-d)δ9.74(s,1H),9.08(s,1H),8.78–8.71(m,1H),7.53(d,J=8.0Hz, 1H),7.39–7.35(m,1H),7.31(s,1H),7.10(dd,J=8.1,1.5Hz,1H),6.32(dd,J=2.0,0.9Hz,1H), 4.76(d,J=5.8Hz,2H),4.11(s,3H),3.98–3.90(m,2H),2.65(d,J=7.3Hz,2H),2.48(dq,J=15. 2,7.7Hz,1H),2.04(dddd,J=11.3,9.2,7.8,4.5Hz,2H),1.95–1.80(m,2H),1.69–1.63(m,2H). ESI-MS m / z:402.0[MH] - .

[0354] Example 5: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (Compound 5)

[0355]

[0356] Compound 5, a white solid, was prepared from intermediate A5 using the method described in Compound 1.

[0357] 1H NMR(500MHz,Methanol-d4)δ9.54(s,1H),9.09(s,1H),8.32(s,1H),7.54(dd,J= 8.2,0.7Hz,1H),7.45(dd,J=1.6,0.9Hz,1H),7.12(dd,J=8.2,1.5Hz,1H),6.62(d ,J=0.8Hz,1H),4.69(s,2H),4.34(s,2H),4.00(s,3H),3.09(d,J=7.5Hz,2H),2. 68(hept,J=7.8Hz,1H),2.22–2.11(m,2H),2.05–1.93(m,1H),1.93–1.77(m,3H). ESI-MS m / z: 403.0 [M+H] + .

[0358] Example 6: Synthesis of N-((2-((((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 6)

[0359]

[0360] Compound 6, a yellow solid, was prepared from intermediate A6 using the method described in Compound 1.

[0361] 1 H NMR (500MHz, Methanol-d4) δ7.42 (dd, J=8.1, 0.7Hz, 1H), 7.30 (dt, J=1.6, 0.8Hz, 1H) ,6.99(dd,J=8.1,1.5Hz,1H),6.31(d,J=0.9Hz,1H),4.58(s,2H),3.99(d,J=1.3Hz,2H ),3.90–3.84(m,2H),3.74(s,3H),3.04(t,J=5.9Hz,2H),2.68–2.62(m,4H),2.55–2.4 5(m,1H),2.12–2.02(m,2H),1.96–1.87(m,1H),1.87–1.79(m,1H),1.73–1.63(m,2H). ESI-MS m / z:407.1[M+H] + .

[0362] Example 7: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-indazole-3-carboxamide (Compound 7)

[0363]

[0364] Compound 7, a white solid, was prepared from 1-methyl-3-indazolecarboxylic acid using the method described in Compound 1.

[0365] 1 H NMR(500MHz, Methanol-d4)δ8.23(dt,J=8.2,1.1Hz,1H),7.56(dd,J=8.5,5.1Hz,1H),7.47–7.41(m ,2H),7.39–7.35(m,1H),7.26(dddd,J=8.0,6.9,2.4,0.9Hz,1H),7.05(dd,J=8.1,1.5Hz,1H),6.31( t,J=1.0Hz,1H),4.69(s,2H),4.09(d,J=4.7Hz,3H),3.85(d,J=1.8Hz,2H),2.61(dd,J=7.4,1.9Hz, 2H),2.54–2.43(m,1H),2.10–2.02(m,2H),1.96–1.86(m,1H),1.85–1.75(m,1H),1.70–1.62(m,2H). ESI-MS m / z:402.2[M+H] + .

[0366] Example 8: Synthesis of N-((2-((((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (Compound 8)

[0367]

[0368] Compound 8, a white solid, was prepared from 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid using the method described in Compound 1.

[0369] 1H NMR(500MHz,Methanol-d4)δ8.62–8.53(m,2H),7.43(d,J=8.1Hz,1H),7.38–7.35(m,1H), 7.30(dd,J=8.1,4.6Hz,1H),7.04(dd,J=8.2,1.5Hz,1H),6.30(d,J=1.1Hz,1H),4.69(s,2 H),4.14(d,J=4.6Hz,3H),3.85(d,J=2.4Hz,2H),2.61(dd,J=7.4,2.5Hz,2H),2.48(hept, J=7.7Hz,1H),2.10–2.02(m,2H),1.96–1.86(m,1H),1.85–1.74(m,1H),1.70–1.60(m,2H). ESI-MS m / z:403.3[M+H] + .

[0370] Example 9: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 9)

[0371]

[0372] Compound 9, a white solid, was prepared from intermediate A7 using the method described in Compound 1.

[0373] 1 H NMR(500MHz,Methanol-d4)δ9.10(d,J=1.3Hz,1H),8.32(d,J=5.7Hz,1H),8.17(dd,J=5.7 ,1.3Hz,1H),7.43(d,J=8.1Hz,1H),7.38–7.33(m,1H),7.04(dd,J=8.1,1.5Hz,1H),6.30(d ,J=1.0Hz,1H),4.70(s,2H),4.24(s,3H),3.85(s,2H),2.61(d,J=7.3Hz,2H),2.49(hept, J=7.7Hz,1H),2.10–2.02(m,2H),1.95–1.86(m,1H),1.86–1.75(m,1H),1.70–1.62(m,2H). ESI-MS m / z:403.0[M+H] + .

[0374] Example 12: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)imidazo[1,5-a]pyrazine-1-carboxamide (Compound 12)

[0375]

[0376] Compound 12, a white solid, was prepared from intermediate A8 using the method described in Compound 1.

[0377] 1 H NMR(500MHz,Methanol-d4)δ9.52(d,J=1.7Hz,1H),8.38(s,1H),8.26(dd,J=5.0,1.7Hz,1H), 7.66(d,J=5.0Hz,1H),7.43(d,J=8.1Hz,1H),7.35(dt,J=1.6,0.9Hz,1H),7.03(dd,J=8.1,1. 5Hz,1H),6.30(d,J=0.9Hz,1H),4.69(s,2H),3.85(s,2H),2.61(d,J=7.3Hz,2H),2.49(dt,J= 15.3,7.8Hz,1H),2.11–2.03(m,2H),1.96–1.85(m,1H),1.85–1.76(m,1H),1.71–1.63(m,2H). ESI-MS m / z:389.0[M+H] + .

[0378] Example 13: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-3-methylimidazo[1,5-a]pyrazine-1-carboxamide (Compound 13)

[0379]

[0380] Compound 13, a white solid, was prepared from intermediate A9 using the method described in Compound 1.

[0381] 1H NMR (600MHz, DMSO-d6) δ10.83(d,J=2.3Hz,1H),9.43(d,J=1.6Hz,1H),8.76(t,J=6.4Hz,1H),8.26 (dd,J=5.0,1.6Hz,1H),7.72(d,J=5.0Hz,1H),7.35(d,J=8.1Hz,1H),7.30(s,1H),6.96(dd,J=8.1 ,1.5Hz,1H),6.21–6.16(m,1H),4.54(d,J=6.3Hz,2H),3.77(s,2H),2.66(s,3H),2.52–2.51(m,2H ), 2.39 (p, J = 7.5Hz, 1H), 1.96 (tdd, J = 7.9, 4.9, 3.1Hz, 2H), 1.85–1.74 (m, 2H), 1.64–1.56 (m, 2H). ESI-MS m / z:403.2[M+H] + .

[0382] Example 16: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-ethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 16)

[0383]

[0384] Compound 16, a white solid, was prepared from intermediate A10 using the method described in Compound 1.

[0385] 1 H NMR(500MHz,Methanol-d4)δ9.71(s,1H),8.58(d,J=6.9Hz,1H),8.27(d,J=6.9Hz,1H),7.5 6–7.51(m,1H),7.47(dt,J=1.6,0.8Hz,1H),7.15(dd,J=8.2,1.5Hz,1H),6.61(d,J=0.9Hz, 1H),4.74(s,2H),4.69(q,J=7.3Hz,2H),4.34(s,2H),3.08(d,J=7.5Hz,2H),2.68(hept,J= 7.8Hz,1H),2.21–2.12(m,2H),2.04–1.93(m,1H),1.91–1.78(m,3H),1.61(t,J=7.3Hz,3H). ESI-MS m / z:417.0[M+H] + .

[0386] Example 17: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-isopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 17)

[0387]

[0388] Compound 17, a white solid, was prepared from intermediate A12 using the method described in Compound 1.

[0389] 1 H NMR (500MHz, Methanol-d4) δ9.72(s,1H),8.58(d,J=6.9Hz,1H),8.31(d,J=6.9Hz,1H),7. 56–7.52(m,1H),7.50–7.46(m,1H),7.16(dd,J=8.2,1.5Hz,1H),6.62(d,J=0.9Hz,1H),5. 24(hept,J=6.6Hz,1H),4.75(s,2H),4.34(s,2H),3.08(d,J=7.5Hz,2H),2.68(hept,J=7. 6Hz,1H),2.22–2.13(m,2H),2.04–1.94(m,1H),1.92–1.79(m,3H),1.67(d,J=6.6Hz,6H). ESI-MS m / z:431.1[M+H] + .

[0390] Example 18: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 18)

[0391]

[0392] Compound 18, a white solid, was prepared from intermediate A14 using the method described in Compound 1.

[0393] 1H NMR (600MHz, Methanol-d4) δ9.78 (s, 1H), 8.69 (s, 1H), 8.30 (d, J = 6.5Hz, 1H), 7.53 (d,J=8.2Hz,1H),7.47(s,1H),7.14(dd,J=8.3,1.5Hz,1H),6.61(s,1H),5.58(q,J =8.5Hz,2H),4.74(s,2H),4.33(s,2H),3.08(d,J=7.5Hz,2H),2.67(hept,J=7.7Hz ,1H),2.21–2.12(m,2H),2.05–1.92(m,1H),1.93–1.85(m,1H),1.86–1.75(m,2H). ESI-MS m / z: 470.9 [M+H] + .

[0394] Example 19: Synthesis of N-((2-((((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 19)

[0395]

[0396] Compound 19, a white solid, was prepared from intermediate A15 using the method described in Compound 1.

[0397] 1 H NMR (500MHz, Methanol-d4) δ9.54–9.49(m,1H),8.44(d,J=6.2Hz,1H),7.72(dd,J=6.2,1.2H z,1H),7.44(d,J=8.1Hz,1H),7.41–7.36(m,1H),7.06(dd,J=8.1,1.5Hz,1H),6.49–6.16(m,2 H),4.94(td,J=14.5,3.7Hz,2H),4.71(s,2H),3.86(s,2H),2.62(d,J=7.3Hz,2H),2.49(hep t,J=7.6Hz,1H),2.11–2.02(m,2H),1.95–1.86(m,1H),1.86–1.77(m,1H),1.71–1.62(m,2H). ESI-MS m / z:453.0[M+H] + .

[0398] Example 20: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-(methyl-d3)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 20)

[0399]

[0400] Compound 20, a white solid, was prepared from intermediate A16 using the method described in Compound 1.

[0401] 1 H NMR (500MHz, Methanol-d4) δ9.45 (d, J=1.2Hz, 1H), 8.36 (d, J=6.2Hz, 1H), 7.60 (dd, J= 6.2,1.2Hz,1H),7.43(d,J=8.1Hz,1H),7.38–7.32(m,1H),7.05(dd,J=8.1,1.5Hz,1H) ,6.29(d,J=0.9Hz,1H),4.69(s,2H),3.84(s,2H),2.64–2.56(m,2H),2.48(hept,J=7. 7Hz,1H),2.10–2.02(m,2H),1.96–1.86(m,1H),1.84–1.74(m,1H),1.70–1.58(m,2H). ESI-MS m / z:406.1[M+H] + .

[0402] Example 21: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 21)

[0403]

[0404] Compound 21, a white solid, was prepared from intermediate A3 using the method described in Compound 1.

[0405] 1H NMR(500MHz, Methanol-d4)δ9.57(s,1H),8.32(s,1H),8.13(s,1H),7.64–7.59(m,1H),7.54(s,1H),7.20(dd,J=8.2,1.5Hz,1H),6.64(s,1H),4 .80(s,2H),4.52(s,3H),4.36(s,2H),3.09(d,J=7.5Hz,2H),2.68(hept ,J=7.7Hz,1H),2.21–2.14(m,3H),2.05–2.01(m,1H),1.92–1.84(m,2H). ESI-MS m / z:403.1[M+H] + .

[0406] Example 22: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2-ethyl-2H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 22)

[0407]

[0408] Compound 22, a white solid, was prepared from intermediate A11 using the method described in Compound 1.

[0409] 1 H NMR (500MHz, Methanol-d4) δ9.14(d,J=1.3Hz,1H),8.22(d,J=6.3Hz,1H),7.63(dd,J=6.4,1.3H z,1H),7.51(d,J=8.1Hz,1H),7.47–7.42(m,1H),7.12(dd,J=8.1,1.5Hz,1H),6.38(s,1H),4.79 (q,J=7.2Hz,2H),4.76(s,2H),3.93(s,2H),2.69(d,J=7.3Hz,2H),2.53(hept,J=8.0Hz,1H),2. 12–2.05(m,2H),1.96–1.89(m,1H),1.87–1.78(m,1H),1.76–1.65(m,2H),1.57(t,J=7.2Hz,3H). ESI-MS m / z:417.3[M+H] + .

[0410] Example 23: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2-isopropyl-2H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 23)

[0411]

[0412] Compound 23, a white solid, was prepared from intermediate A13 using the method described in Compound 1.

[0413] 1 H NMR (500MHz, Methanol-d4) δ9.55 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 6.8Hz, 1H), 7.60 ( d,J=8.2Hz,1H),7.54(s,1H),7.20(dd,J=8.2,1.5Hz,1H),6.65(s,1H),5.56(hept,J =6.4Hz,1H),4.80(s,2H),4.36(s,2H),3.10(d,J=7.5Hz,2H),2.69(hept,J=7.8Hz, 1H), 2.17–2.13 (m, 1H), 2.07–2.01 (m, 2H), 1.92–1.81 (m, 3H), 1.67 (d, J = 6.6Hz, 6H). ESI-MS m / z: 431.1 [M+H] + .

[0414] Example 24: Synthesis of N-((2-((((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 24)

[0415]

[0416] Compound 24, a white solid, was prepared from intermediate A17 using the method described in Compound 1.

[0417] 1 H NMR (500MHz, Methanol-d4) δ9.33 (s, 1H), 8.11 (s, 1H), 7.44 (d, J = 8.1Hz, 1H), 7.37(s,1H),7.05(dd,J=8.2,1.5Hz,1H),6.31(s,1H),4.69(s,2H),4.36(s,3 H),3.86(s,2H),2.76(s,3H),2.63(d,J=7.3Hz,2H),2.50(hept,J=7.7Hz,1H) ,2.10–2.04(m,2H),1.95–1.87(m,1H),1.87–1.77(m,1H),1.73–1.64(m,2H). ESI-MS m / z: 417.1 [M+H] + .

[0418] Example 26: Synthesis of N-((2-((isobutylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 26)

[0419]

[0420] Compound 26, a white solid, was prepared from intermediate 3-2 and isobutylamine using the method described in Compound 3.

[0421] 1 H NMR(500MHz,Methanol-d4)δ9.50–9.44(m,1H),8.38(d,J=6.2Hz,1H),7.63(dd ,J=6.2,1.2Hz,1H),7.44(dd,J=8.1,0.7Hz,1H),7.37(dt,J=1.7,0.8Hz,1H),7. 05(dd,J=8.1,1.5Hz,1H),6.31(d,J=0.9Hz,1H),4.70(s,2H),4.13(s,3H),3.9 0–3.84(m,2H),2.41(d,J=6.9Hz,2H),1.84–1.70(m,1H),0.90(d,J=6.7Hz,6H). ESI-MS m / z: 391.0 [M+H] + .

[0422] Example 27: Synthesis of 1-methyl-N-((2-((neopentylamino)methyl)-1H-indol-6-yl)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 27)

[0423]

[0424] Compound 27, a white solid, was prepared from intermediate 3-2 and pentylamine using the method described in Compound 3.

[0425] 1H NMR(500MHz, Methanol-d4)δ9.46(s,1H),8.38(d,J=6.2Hz,1H),7.62(dd,J=6.2,1.2Hz,1H),7.44(d,J=8.1Hz,1H),7.40–7.3 4(m,1H),7.05(dd,J=8.2,1.5Hz,1H),6.29(d,J=1.0Hz,1H),4.70(s,2H),4.12(s,3H),3.87(s,2H),2.35(s,2H),0.90(s,9H). ESI-MS m / z:405.0[M+H] + .

[0426] Example 28: Synthesis of N-((2-(((cyclopropylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 28)

[0427]

[0428] Compound 28, a white solid, was prepared from intermediate 3-2 and cyclopropylmethylamine using the method described in Compound 3.

[0429] 1 H NMR (600MHz, Methanol-d4) δ9.46(s,1H),8.38(d,J=6.1Hz,1H),7.63(dd,J=6.1,1.3Hz,1H),7.44(d,J=8.1Hz,1H),7.37(s,1H),7.05(dd,J=8.1 ,1.6Hz,1H),6.31(s,1H),4.69(s,2H),4.12(s,3H),3.92(s,2H),2.46(d ,J=7.0Hz,2H),1.01–0.92(m,1H),0.53–0.46(m,2H),0.15–0.09(m,2H). ESI-MS m / z:389.0[M+H] + .

[0430] Example 29: Synthesis of N-((2-(((cyclopentylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 29)

[0431]

[0432] Compound 29, a white solid, was prepared from intermediate 3-2 and cyclopentylmethylamine using the method described in Compound 3.

[0433] 1 H NMR(500MHz,Methanol-d4)δ9.46(d,J=1.2Hz,1H),8.38(d,J=6.2Hz,1H),7.63(dd ,J=6.2,1.2Hz,1H),7.44(d,J=8.1Hz,1H),7.40–7.37(m,1H),7.05(dd,J=8.1,1.5 Hz,1H),6.34–6.29(m,1H),4.70(s,2H),4.13(s,3H),3.89(s,2H),2.54(d,J=7.2H z,2H),2.07–1.99(m,1H),1.82–1.73(m,2H),1.63–1.49(m,4H),1.19–1.08(m,2H). ESI-MS m / z: 416.9 [M+H] + .

[0434] Example 30: Synthesis of N-((2-(((cyclohexylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 30)

[0435]

[0436] Compound 30, a white solid, was prepared from intermediate 3-2 and cyclohexylmethylamine using the method described in Compound 3.

[0437] 1 H NMR(600MHz,Methanol-d4)δ9.71(s,1H),8.59(d,J=6.9Hz,1H),8.25(d,J=6.9H z,1H),7.53(d,J=8.2Hz,1H),7.46(s,1H),7.14(dd,J=8.2,1.5Hz,1H),6.62(s,1 H),4.74(s,2H),4.36(s,2H),4.31(s,3H),2.88(d,J=7.0Hz,2H),1.82–1.73(m, 4H),1.73–1.64(m,2H),1.36–1.31(m,2H),1.25–1.16(m,1H),1.06–0.97(m,2H). ESI-MS m / z: 431.1 [M+H] + .

[0438] Example 31: Synthesis of N-((2-((benzylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 31)

[0439]

[0440] Compound 31, a white solid, was prepared from intermediate 3-2 and benzylamine using the method described in Compound 3.

[0441] 1 H NMR(600MHz,DMSO-d6)δ10.90(d,J=2.2Hz,1H),9.43(s,1H),9.08(t,J=6.3Hz,1H),8.4 5(d,J=6.0Hz,1H),7.76(dd,J=6.0,1.3Hz,1H),7.38(d,J=8.1Hz,1H),7.34(d,J=6.2Hz, 3H),7.30(t,J=7.5Hz,2H),7.21(t,J=7.1Hz,1H),6.99(dd,J=8.1,1.5Hz,1H),6.23(d,J =2.0Hz,1H),4.57(d,J=6.3Hz,2H),4.13(s,3H),3.79(s,2H),3.68(s,2H),2.65(s,1H). ESI-MS m / z:424.9[M+H] + .

[0442] Example 32: Synthesis of 1-methyl-N-((2-(((((1-methylcyclopropyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 32)

[0443]

[0444] Compound 32, a white solid, was prepared from intermediate 3-2 and (1-methylcyclopropyl)methylamine hydrochloride using the method described in Compound 3.

[0445] 1 H NMR(500MHz, Methanol-d4)δ9.47(s,1H),8.38(d,J=5.8Hz,1H),7.63(d,J=6.0Hz,1H),7.43(dd,J=8.1,0.7Hz,1H),7.39–7.32(m,1H),7.05(dd, J=8.1,1.5Hz,1H),6.30(d,J=0.9Hz,1H),4.70(s,2H),4.12(s,3H),3.89 (s,2H),2.44(s,2H),1.11(s,3H),0.34–0.30(m,2H),0.29–0.26(m,2H). ESI-MS m / z:403.0[M+H]+ .

[0446] Example 33: Synthesis of 1-methyl-N-((2-(((oxecyclobutane-2-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 33)

[0447]

[0448] Compound 33, a white solid, was prepared from intermediate 3-2 and oxetane-2-methylamine using the method described in Compound 3.

[0449] 1 H NMR (500MHz, DMSO-d6) δ10.87(d,J=2.2Hz,1H),9.42(d,J=1.2Hz,1H),9.06(t,J=6.3Hz,1H),8.45(d,J=6. 0Hz,1H),7.75(dd,J=6.1,1.3Hz,1H),7.37(d,J=8.1Hz,1H),7.33(s,1H),6.99(dd,J=8.1,1.5Hz,1H),6.26 –6.16(m,1H),4.82–4.69(m,1H),4.56(d,J=6.3Hz,2H),4.47(td,J=7.8,5.8Hz,1H),4.36(dt,J=9.0,5.8H z,1H),4.13(s,3H),3.83(s,2H),2.79–2.65(m,2H),2.59–2.51(m,1H),2.38(ddt,J=10.6,8.8,7.0Hz,1H). ESI-MS m / z:405.0[M+H] + .

[0450] Example 34: Synthesis of N-((2-((((1-hydroxycyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 34)

[0451]

[0452] Compound 34, a white solid, was prepared from intermediates 3-2 and 1-(aminomethyl)cyclobutanol using the method described in Compound 3.

[0453] 1H NMR(500MHz,Methanol-d4)δ9.46(d,J=1.2Hz,1H),8.38(d,J=6.2Hz,1H),7.63(d d,J=6.2,1.2Hz,1H),7.44(dd,J=8.2,0.7Hz,1H),7.37(dt,J=1.6,0.8Hz,1H),7.0 5(dd,J=8.1,1.5Hz,1H),6.31(d,J=0.9Hz,1H),4.70(s,2H),4.13(s,3H),3.96–3 .92(m,2H),2.71(s,2H),2.10–2.04(m,2H),1.77–1.68(m,1H),1.53–1.43(m,1H). ESI-MS m / z: 419.1 [M+H] + .

[0454] Example 35: Synthesis of 1-methyl-N-((2-(((((3-methylcyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 35)

[0455]

[0456] Compound 35, a white solid, was prepared from intermediate 3-2 and (3-methylcyclobutyl)methylamine using the method described in Compound 3.

[0457] 1 H NMR(500MHz,Methanol-d4)δ9.46(d,J=1.2Hz,1H),8.37(d,J=6.2Hz,1H),7.62(dd,J=6.2,1.2Hz,1H) ,7.44(d,J=8.1Hz,1H),7.37(dt,J=1.6,0.9Hz,1H),7.05(dd,J=8.1,1.5Hz,1H),6.30(dd,J=3.9,0.9H z,1H),4.70(s,2H),4.12(s,3H),3.85(dd,J=10.4,0.7Hz,2H),2.65(d,J=7.6Hz,1H),2.56(d,J=6.9H z,1H),2.37–2.16(m,3H),1.86–1.78(m,1H),1.73–1.66(m,1H),1.24–1.19(m,1H),1.09–0.96(m,3H). ESI-MS m / z:417.0[M+H] + .

[0458] Example 36: Synthesis of N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 36)

[0459]

[0460] Compound 36, a white solid, was prepared from intermediate 3-2 and (3,3-difluorocyclobutyl)methylamine hydrochloride using the method described in Compound 3.

[0461] 1 H NMR (500MHz, Methanol-d4) δ9.47 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.1 ,1.1Hz,1H),7.44(dd,J=8.1,0.7Hz,1H),7.37(dt,J=1.6,0.8Hz,1H),7.05(dd, J=8.1,1.5Hz,1H),6.31(d,J=0.8Hz,1H),4.70(s,2H),4.13(s,3H),3.88(s,2H) ,2.70(d,J=7.1Hz,2H),2.67–2.57(m,2H),2.36–2.24(m,1H),2.23–2.15(m,2H). ESI-MS m / z: 439.1 [M+H] + .

[0462] Example 37: Synthesis of N-((2-((((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 37)

[0463]

[0464] Compound 37, a white solid, was prepared from intermediate 3-2 and (3-fluorobicyclo[1.1.1]pent-1-yl)methylamine hydrochloride using the method described in Compound 3.

[0465] 1H NMR (500MHz, Methanol-d4) δ9.47(s,1H),8.38(d,J=6.1Hz,1H),7.64(dd,J=6.2,1.2Hz,1H),7.44(dd,J=8.1,0.7Hz,1H),7.37(dt,J=1.6, 0.8Hz,1H),7.05(dd,J=8.1,1.5Hz,1H),6.30(d,J=0.9Hz,1H),4.70(s,2H),4.13(s,3H),3.89(s,2H),2.85(s,2H),1.95(d,J=2.6Hz,6H). ESI-MS m / z:433.1[M+H] + .

[0466] Example 38: Synthesis of N-((2-((((1-hydroxycyclopentyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 38)

[0467]

[0468] Compound 38, a white solid, was prepared from intermediates 3-2 and 1-(aminomethyl)cyclopentanol hydrochloride using the method described in Compound 3.

[0469] 1 H NMR(500MHz,DMSO-d6)δ10.86–10.75(m,1H),9.43(s,1H),9.05(t,J=6.3Hz,1H),8.45( d,J=6.0Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.35(d,J=8.1Hz,1H),7.32(dt,J=1.6,0. 8Hz,1H),6.97(dd,J=8.1,1.5Hz,1H),6.18(d,J=1.8Hz,1H),4.56(d,J=6.2Hz,2H),4.5 1(s,1H),4.13(s,3H),3.75(s,2H),3.32(s,2H),1.71–1.62(m,2H),1.54–1.45(m,6H). ESI-MS m / z:433.0[M+H] + .

[0470] Example 39: Synthesis of N-((2-(((bicyclo[2.2.1]hept-5-en-2-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 39)

[0471]

[0472] Compound 39, a white solid, was prepared from intermediates 3-2 and 5-norbornene-2-methylamine using the method described in Compound 3.

[0473] 1 H NMR(500MHz,Methanol-d4)δ9.46(d,J=1.3Hz,1H),8.37(d,J=6.2Hz,1H),7.62(dd,J=6.2,1.2Hz,1H),7.46–7.41 (m,1H),7.37(dt,J=1.6,0.8Hz,1H),7.05(dd,J=8.1,1.5Hz,1H),6.29(d,J=0.9Hz,1H),6.06(dd,J=5.8,3.1Hz,1H ),5.84(dd,J=5.8,2.9Hz,1H),4.70(s,2H),4.12(s,3H),3.90–3.79(m,2H),2.89–2.81(m,1H),2.76–2.68(m,1H), 2.37–2.26(m,2H),2.25–2.17(m,1H),1.91–1.73(m,1H),1.42–1.36(m,1H),1.26–1.23(m,1H),0.52–0.47(m,1H). ESI-MS m / z:441.0[M+H] + .

[0474] Example 40: Synthesis of N-((2-(((((3r,5r,7r)-adamantane-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl ester)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 40)

[0475]

[0476] Compound 40, a white solid, was prepared from intermediates 3-2 and 1-aminomethyladamantane using the method described in Compound 3.

[0477] 1H NMR(500MHz,Methanol-d4)δ9.46(d,J=1.2Hz,1H),8.37(d,J=6.2Hz,1H),7.61(d d,J=6.2,1.2Hz,1H),7.44(d,J=8.1Hz,1H),7.40–7.36(m,1H),7.05(dd,J=8.1,1. 5Hz,1H),6.29(d,J=0.9Hz,1H),4.69(s,2H),4.12(s,3H),3.85(s,2H),2.23(s,2H ),1.94–1.89(m,3H),1.76–1.69(m,3H),1.66–1.62(m,3H),1.51(d,J=2.8Hz,6H). ESI-MS m / z: 483.0 [M+H] + .

[0478] Example 41: Synthesis of N-((2-((cyclopropylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 41)

[0479]

[0480] Compound 41, a white solid, was prepared from intermediate 3-2 and cyclopropylamine using the method described in Compound 3.

[0481] 1 H NMR (500MHz, DMSO-d6) δ10.82(d,J=2.0Hz,1H),9.42(d,J=1.2Hz,1H),9.05(t,J=6.3Hz,1 H),8.45(d,J=6.1Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.33–7.31( m,1H),6.98(dd,J=8.1,1.5Hz,1H),6.23–6.18(m,1H),4.59–4.52(m,2H),4.13(s,3H),3. 81(s,2H),2.58(s,1H),2.06(tt,J=6.7,3.6Hz,1H),0.36–0.30(m,2H),0.27–0.21(m,2H). ESI-MS m / z:375.0[M+H] + .

[0482] Example 42: Synthesis of N-((2-((cyclobutylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 42)

[0483]

[0484] Compound 42, a white solid, was prepared from intermediate 3-2 and cyclobutamine using the method described in Compound 3.

[0485] 1 H NMR(500MHz, Methanol-d4)δ9.49–9.43(m,1H),8.37(d,J=6.2Hz,1H),7.61(dd,J=6.2,1.2Hz,1H),7.43(dd,J=8.1,0.7Hz,1H),7.36(dt,J=1.6,0.8Hz,1H) ,7.04(dd,J=8.1,1.5Hz,1H),6.29(q,J=0.8Hz,1H),4.69(s,2H),4.11(s,3H) ,3.80–3.75(m,2H),3.30–3.22(m,1H),2.21–2.12(m,2H),1.80–1.60(m,4H). ESI-MS m / z: 388.9 [M+H] + .

[0486] Example 43: Synthesis of N-((2-((cyclopentylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 43)

[0487]

[0488] Compound 43, a white solid, was prepared from intermediate 3-2 and cyclopentylamine using the method described in Compound 3.

[0489] 1H NMR(500MHz,Methanol-d4)δ9.46(d,J=1.3Hz,1H),8.37(d,J=6.2Hz,1H),7.62(dq,J=6.2 ,1.1Hz,1H),7.43(dd,J=8.1,0.7Hz,1H),7.37(dt,J=1.6,0.8Hz,1H),7.05(dd,J=8.1,1. 5Hz,1H),6.31(d,J=0.9Hz,1H),4.69(s,2H),4.12(d,J=0.9Hz,3H),3.87(s,2H),3.08(p, J=7.1Hz,1H),1.94–1.84(m,2H),1.76–1.66(m,2H),1.57–1.47(m,2H),1.42–1.34(m,2H). ESI-MS m / z:403.0[M+H] + .

[0490] Example 44: Synthesis of N-((2-((cyclohexylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 44)

[0491]

[0492] Compound 44, a white solid, was prepared from intermediate 3-2 and cyclohexylamine using the method described in Compound 3.

[0493] 1 H NMR(500MHz,Methanol-d4)δ9.46(s,1H),8.38(d,J=6.2Hz,1H),7.63(dd,J=6.2,1.2Hz, 1H),7.44(dd,J=8.1,0.7Hz,1H),7.37(dt,J=1.6,0.8Hz,1H),7.05(dd,J=8.1,1.5Hz,1H ),6.30(d,J=0.9Hz,1H),4.70(s,2H),4.13(s,3H),3.93–3.88(m,2H),2.46(tt,J=10.6, 3.8Hz,1H),1.99–1.86(m,2H),1.77–1.68(m,2H),1.66–1.56(m,1H),1.26–1.06(m,5H). ESI-MS m / z:416.9[M+H] + .

[0494] Example 45: Synthesis of N-((2-((bicyclo[1.1.1]pent-1-ylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 45)

[0495]

[0496] Compound 45, a white solid, was prepared from intermediate 3-2 and bicyclic [1.1.1]pentane-1-amine hydrochloride using the method described in Compound 3.

[0497] 1 H NMR (500MHz, Methanol-d4) δ9.46(s,1H),8.38(d,J=6.1Hz,1H),7.63(dd,J=6.2,1.2Hz,1H),7.42(dd,J=8.1,0.7Hz,1H),7.36(dt,J=1.6, 0.8Hz,1H),7.04(dd,J=8.1,1.5Hz,1H),6.29(d,J=0.9Hz,1H),4.69(s,2H),4.12(s,3H),3.86(d,J=0.8Hz,2H),2.36(s,1H),1.79(s,6H). ESI-MS m / z:400.9[M+H] + .

[0498] Example 46: Synthesis of N-((2-((adamantane-1-ylamino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 46)

[0499]

[0500] Compound 46, a white solid, was prepared from intermediate 3-2 and adamantane using the method described in Compound 3.

[0501] 1H NMR (600MHz, DMSO-d6) δ10.79(s,1H),9.42(s,1H),9.06(t,J=6.3Hz,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.36–7.31(m,2H),6 .96(dd,J=8.1,1.5Hz,1H),6.17(s,1H),4.55(d,J=6.2Hz,2H),4.13(s,3 H),3.81(s,2H),2.01–1.99(m,3H),1.63–1.59(m,9H),1.57–1.53(m,3H). ESI-MS m / z:469.1[M+H] + .

[0502] Example 47: Synthesis of N-((2-(((cyclobutylmethyl)(methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 47)

[0503]

[0504] Compound 47, a white solid, was prepared from intermediates 3-2 and 1-cyclobutyl-N-methylmethylamine hydrochloride using the method described in Compound 3.

[0505] 1 H NMR(500MHz,Methanol-d4)δ9.45(s,1H),8.37(d,J=6.1Hz,1H),7.61(dd,J=6.1,1.2Hz,1 H),7.44(d,J=8.1Hz,1H),7.41–7.36(m,1H),7.05(dd,J=8.2,1.5Hz,1H),6.32–6.25(m,1H ),4.69(s,2H),4.11(s,3H),3.62(s,2H),2.58(hept,J=7.7Hz,1H),2.44(d,J=7.0Hz,2H) ,2.20(s,3H),2.10–2.03(m,2H),1.96–1.84(m,1H),1.80–1.72(m,1H),1.72–1.61(m,2H). ESI-MS m / z:417.0[M+H] + .

[0506] Example 48: Synthesis of 1-methyl-N-((2-(piperidin-1-ylmethyl)-1H-indol-6-yl)methyl)-1Hpyrazolo[4,3-c]pyridine-3-carboxamide (Compound 48)

[0507]

[0508] Compound 48, a white solid, was prepared from intermediate 3-2 and piperidine using the method described in Compound 3.

[0509] 1 H NMR(500MHz, Methanol-d4)δ9.46(s,1H),8.37(d,J=6.1Hz,1H),7.62(dd,J=6.2,1.2Hz,1H),7.44(d,J=8.1Hz,1H),7.40–7.36(m,1H),7.05 (dd,J=8.1,1.5Hz,1H),6.29(d,J=0.9Hz,1H),4.69(s,2H),4.12(s,3H),3.62(s,2H),2.45(s,4H),1.59(p,J=5.7Hz,4H),1.48–1.40(m,2H). ESI-MS m / z:403.0[M+H] + .

[0510] Example 49: Synthesis of N-((2-((4-fluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 49)

[0511]

[0512] Compound 49, a white solid, was prepared from intermediates 3-2 and 4-fluoropiperidine using the method described in Compound 3.

[0513] 1 H NMR (600MHz, DMSO-d6) δ10.93(d,J=2.2Hz,1H),9.45–9.38(m,1H),9.08(t,J=6.3Hz,1H),8.45(d ,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.37(d,J=8.1Hz,1H),7.33(s,1H),6.99(dd,J=8.1,1 .5Hz,1H),6.21(d,J=2.0Hz,1H),4.66(dtt,J=49.0,7.4,3.6Hz,1H),4.55(d,J=6.1Hz,2H),4.14 (s,3H),3.58(s,2H),2.58–2.51(m,2H),2.35–2.22(m,2H),1.90–1.77(m,2H),1.74–1.65(m,2H). ESI-MS m / z:421.0[M+H]+ .

[0514] Example 50: Synthesis of N-((2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 50)

[0515]

[0516] Compound 50, a white solid, was prepared from intermediates 3-2 and 4,4-difluoropiperidine using the method described in Compound 3.

[0517] 1 H NMR(600MHz,DMSO-d6)δ10.95(d,J=2.2Hz,1H),9.45–9.39(m,1H),9.09(t,J =6.3Hz,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.38(d,J=8 .1Hz,1H),7.33(s,1H),6.99(dd,J=8.1,1.5Hz,1H),6.24(s,1H),4.56(d,J= 5.5Hz,2H),4.14(s,3H),3.66(s,2H),2.50–2.46(m,4H),1.98–1.91(m,4H). ESI-MS m / z: 439.1 [M+H] + .

[0518] Example 51: Synthesis of N-((2-(((4,4-dimethylcyclohexyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 51)

[0519]

[0520] Compound 51, a white solid, was prepared from intermediates 3-2 and 4,4-dimethylpiperidine using the method described in Compound 3.

[0521] 1H NMR (500MHz, Methanol-d4) δ9.46(d,J=1.2Hz,1H),8.37(d,J=6.1Hz,1H),7.62(dd,J=6.2,1.2Hz,1H),7.44(d,J=8.1Hz,1H),7.40–7.35( m,1H),7.05(dd,J=8.1,1.5Hz,1H),6.30(s,1H),4.69(s,2H),4.12(s,3H),3.67(s,2H),2.48(s,4H),1.41(t,J=5.7Hz,4H),0.90(s,6H). ESI-MS m / z:431.2[M+H] + .

[0522] Example 52: Synthesis of N-((2-((6-azaspiro[2.5]octane-6-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 52)

[0523]

[0524] Compound 52, a white solid, was prepared from intermediates 3-2 and 6-azaspiro[2.5]octane hydrochloride using the method described in Compound 3.

[0525] 1 H NMR (500MHz, DMSO-d6) δ10.92(d,J=2.1Hz,1H),9.42(d,J=1.2Hz,1H),9.06(t,J=6 .3Hz,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.2Hz,1H),7.37(d,J=8.1Hz,1H) ,7.35–7.32(m,1H),6.99(dd,J=8.1,1.5Hz,1H),6.21(dd,J=2.0,0.9Hz,1H),4.56 (d,J=6.3Hz,2H),4.13(s,3H),3.59(s,2H),2.40(s,4H),1.32(s,4H),0.21(s,4H). ESI-MS m / z: 429.1 [M+H] + .

[0526] Example 53: Synthesis of 1-methyl-N-((2-(morpholinomethyl)-1H-indol-6-yl)methyl)-1Hpyrazolo[4,3-c]pyridine-3-carboxamide (Compound 53)

[0527]

[0528] Compound 53, a white solid, was prepared from intermediate 3-2 and morpholine using the method described in Compound 3.

[0529] 1 H NMR(600MHz,DMSO-d6)δ10.95(d,J=2.2Hz,1H),9.45–9.36(m,1H),9.08(t,J =6.3Hz,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.0,1.3Hz,1H),7.37(d,J=8 .1Hz,1H),7.33(s,1H),6.99(dd,J=8.1,1.5Hz,1H),6.23(d,J=2.0Hz,1H),4 .55(d,J=6.0Hz,2H),4.13(s,3H),3.58–3.55(m,6H),2.36(t,J=4.6Hz,4H). ESI-MS m / z: 405.0 [M+H] + .

[0530] Example 54: Synthesis of N-((2-((2-azabicyclo[2.2.1]heptane-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 54)

[0531]

[0532] Compound 54, a white solid, was prepared from intermediates 3-2 and 2-azabicyclo[2.2.1]heptane hydrochloride using the method described in Compound 3.

[0533] 1 H NMR (500MHz, Methanol-d4) δ9.46 (s, 1H), 8.38 (d, J = 6.1Hz, 1H), 7.63 (dd, J = 6.2, 1.2Hz, 1H), 7. 43(d,J=8.1Hz,1H),7.37(d,J=1.4Hz,1H),7.05(dd,J=8.2,1.5Hz,1H),6.31(s,1H),4.69(s,2H ),4.12(s,3H),3.82–3.70(m,2H),3.29(d,J=2.6Hz,1H),2.80–2.75(m,1H),2.39–2.34(m,2H), 1.87–1.80(m,1H),1.71–1.66(m,1H),1.65–1.57(m,1H),1.50–1.44(m,1H),1.36–1.32(m,2H). ESI-MS m / z:415.0[M+H]+ .

[0534] Example 55: Synthesis of N-((2-((2-azabicyclo[2.2.2]octane-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 55)

[0535]

[0536] Compound 55, a white solid, was prepared from intermediates 3-2 and 2-azabicyclo[2.2.2]octane hydrochloride using the method described in Compound 3.

[0537] 1 H NMR (600MHz, DMSO-d6) δ10.85(d,J=2.2Hz,1H),9.42(s,1H),9.07(t,J=6.3Hz,1H),8.45(d,J=6.0H z,1H),7.76(dd,J=6.0,1.3Hz,1H),7.35(d,J=8.1Hz,1H),7.32(s,1H),6.97(dd,J=8.1,1.5Hz,1H), 6.20(d,J=2.0Hz,1H),4.55(d,J=6.2Hz,2H),4.13(s,3H),3.70(s,2H),2.64(d,J=2.3Hz,2H),2.05– 1.93(m,1H),1.89(tt,J=12.4,4.0Hz,2H),1.63–1.53(m,3H),1.49–1.42(m,2H),1.42–1.33(m,2H). ESI-MS m / z:429.0[M+H] + .

[0538] Example 56: Synthesis of 1-methyl-N-((2-(pyrrolidone-1-ylmethyl)-1H-indol-6-yl)methyl)-1Hpyrazolo[4,3-c]pyridine-3-carboxamide (Compound 56)

[0539]

[0540] Compound 56, a white solid, was prepared from intermediate 3-2 and tetrahydropyrrole using the method described in Compound 3.

[0541] 1H NMR(500MHz, Methanol-d4)δ9.46(s,1H),8.38(d,J=6.2Hz,1H),7.63(dd,J=6.1,1.2Hz,1H),7.47–7.42(m,1H),7.38(dt,J=1.6,0.8Hz, 1H),7.05(dd,J=8.2,1.5Hz,1H),6.31(d,J=0.9Hz,1H),4.70(s,2H),4.13(s,3H),3.77(s,2H),2.65–2.55(m,4H),1.80(p,J=3.2Hz,4H). ESI-MS m / z:389.0[M+H] + .

[0542] Example 57: Synthesis of N-((2-((2-azabicyclo[2.1.1]hexane-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 57)

[0543]

[0544] Compound 57, a white solid, was prepared from intermediates 3-2 and 2-azabicyclo[2.1.1]hexane hydrochloride using the method described in Compound 3.

[0545] 1 H NMR(500MHz,DMSO-d6)δ10.99–10.90(m,1H),9.42(d,J=1.2Hz,1H),9.06(t,J=6.3Hz,1H),8.4 5(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.36(d,J=8.1Hz,1H),7.35–7.32(m,1H),6.98( dd,J=8.1,1.5Hz,1H),6.21(dd,J=2.0,1.0Hz,1H),4.56(d,J=6.3Hz,2H),4.13(s,3H),3.77(s ,2H),3.39–3.35(m,1H),2.71–2.67(m,1H),2.58(s,2H),1.67–1.61(m,2H),1.45–1.39(m,2H). ESI-MS m / z:401.0[M+H] + .

[0546] Example 58: Synthesis of N-((2-((2,2-dimethylpyrrolidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 58)

[0547]

[0548] Compound 58, a white solid, was prepared from intermediates 3-2 and 2,2-dimethylpyrrolidine using the method described in Compound 3.

[0549] 1 H NMR (500MHz, DMSO-d6) δ10.72(s,1H),9.43(s,1H),9.05(t,J=6.3Hz,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.39–7.32(m,2H),6.9 7(dd,J=8.2,1.4Hz,1H),6.22–6.16(m,1H),4.56(d,J=6.2Hz,2H),4.13(s ,3H),3.60(s,2H),2.56(d,J=7.0Hz,2H),1.68–1.59(m,4H),1.04(s,6H). ESI-MS m / z:417.0[M+H] + .

[0550] Example 59: Synthesis of N-((2-((3,3-dimethylpyrrolidin-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 59)

[0551]

[0552] Compound 59, a white solid, was prepared from intermediates 3-2 and 3,3-dimethylpyrrolidine hydrochloride using the method described in Compound 3.

[0553] 1 H NMR (500MHz, Methanol-d4) δ9.48(s,1H),8.40(d,J=6.1Hz,1H),7.66(dd,J=6.2,1.2Hz,1H),7.44(d,J=8.1Hz,1H),7.39(d,J=1.5Hz,1H),7.05(dd,J= 8.1,1.5Hz,1H),6.30(d,J=0.9Hz,1H),4.71(s,2H),4.14(s,3H),3.74(s,2 H), 2.70 (t, J = 6.9 Hz, 2H), 2.43 (s, 2H), 1.62 (t, J = 6.9 Hz, 2H), 1.08 (s, 6H). ESI-MS m / z:417.0[M+H] + .

[0554] Example 60: Synthesis of N-((2-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 60)

[0555]

[0556] Compound 60, a white solid, was prepared from intermediates 3-2 and 3-azabicyclo[3.1.0]hexane hydrochloride using the method described in Compound 3.

[0557] 1 H NMR (500MHz, DMSO-d6) δ10.84–10.77(m,1H),9.43(s,1H),9.06(t,J=6.3Hz,1H),8.45(d,J=6.0Hz,1 H),7.76(dd,J=6.1,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.32(d,J=1.4Hz,1H),6.98(dd,J=8.1,1.5Hz ,1H),6.16(dd,J=2.0,1.0Hz,1H),4.56(d,J=6.3Hz,2H),4.13(s,3H),3.66(s,2H),2.85(d,J=8.6Hz ,2H),2.33(dt,J=8.6,1.6Hz,2H),1.35–1.30(m,2H),0.74–0.68(m,1H),0.28(td,J=7.6,3.7Hz,1H). ESI-MS m / z:401.0[M+H] + .

[0558] Example 61: Synthesis of N-((2-((hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 61)

[0559]

[0560] Compound 61, a white solid, was prepared from intermediates 3-2 and 3-azabicyclo[3.3.0]octane hydrochloride using the method described in Compound 3.

[0561] 1H NMR (500MHz, DMSO-d6) δ10.94–10.85(m,1H),9.42(d,J=1.3Hz,1H),9.06(t,J=6.3Hz,1H),8.45(d,J=6. 0Hz,1H),7.76(dd,J=6.1,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.32(d,J=1.6Hz,1H),6.98(dd,J=8.1,1.5H z,1H),6.18(dd,J=2.0,0.9Hz,1H),4.55(d,J=6.2Hz,2H),4.13(s,3H),3.58(s,2H),2.60(dd,J=8.8,7. 3Hz,2H),2.49–2.43(m,2H),2.12–2.07(m,2H),1.63–1.53(m,3H),1.48–1.39(m,1H),1.39–1.31(m,2H). ESI-MS m / z:429.1[M+H] + .

[0562] Example 62: Synthesis of N-((2-((5-azaspiro[2.4]hept-5-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 62)

[0563]

[0564] Compound 62, a white solid, was prepared from intermediates 3-2 and 5-azaspiro[2.4]heptane hydrochloride using the method described in Compound 3.

[0565] 1 H NMR (500MHz, DMSO-d6) δ11.00–10.88(m,1H),9.43(d,J=1.2Hz,1H),8.97(t,J=6.3Hz,1H),8.45( d,J=6.0Hz,1H),7.74(dd,J=6.0,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.33(dt,J=1.6,0.8Hz,1H), 6.99(dd,J=8.1,1.5Hz,1H),6.20(dd,J=2.1,1.0Hz,1H),4.56(d,J=6.2Hz,2H),4.13(s,3H),3.6 8(s,2H),2.67(t,J=6.9Hz,2H),2.43(s,2H),1.73(t,J=6.8Hz,2H),0.47(dt,J=10.0,2.0Hz,4H). ESI-MS m / z:415.0[M+H]+ .

[0566] Example 63: Synthesis of N-((2-((6-azaspiro[3,4]octane-6-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 63)

[0567]

[0568] Compound 63, a white solid, was prepared from intermediates 3-2 and 6-azaspiro[3.4]octane hydrochloride using the method described in Compound 3.

[0569] 1 H NMR (600MHz, DMSO-d6) δ10.92(d,J=2.1Hz,1H),9.42(s,1H),9.07(t,J=6.3Hz,1H),8.44(d ,J=6.0Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.32(s,1H),6.98(dd,J= 8.1,1.5Hz,1H),6.23–6.14(m,1H),4.55(d,J=6.2Hz,2H),4.13(s,3H),3.62(s,2H),2.52–2 .50(m,2H),2.49–2.46(m,2H),1.95–1.82(m,4H),1.80(t,J=7.0Hz,2H),1.77–1.66(m,2H). ESI-MS m / z:429.0[M+H] + .

[0570] Example 64: Synthesis of N-((2-((3,3-dimethylazacyclobutane-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 64)

[0571]

[0572] Compound 64, a white solid, was prepared from intermediates 3-2 and 3,3-dimethylaziridine hydrochloride using the method described in Compound 3.

[0573] 1H NMR (500MHz, DMSO-d6) δ10.86(d,J=2.0Hz,1H),9.42(d,J=1.2Hz,1H),9.06(t,J= 6.3Hz,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.36(d,J=8.1Hz,1 H),7.31(dt,J=1.6,0.8Hz,1H),6.98(dd,J=8.1,1.5Hz,1H),6.17(dd,J=2.1,1.0H z, 1H), 4.55 (d, J = 6.3Hz, 2H), 4.13 (s, 3H), 3.61 (s, 2H), 2.89 (s, 4H), 1.15 (s, 6H). ESI-MS m / z: 403.1 [M+H] + .

[0574] Example 65: Synthesis of N-((2-((2-azaspiro[3.3]hept-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 65)

[0575]

[0576] Compound 65, a white solid, was prepared from intermediates 3-2 and 2-azaspiro[3.3]heptane hydrochloride using the method described in Compound 3.

[0577] 1 H NMR(500MHz,DMSO-d6)δ10.89(d,J=2.0Hz,1H),9.42(d,J=1.2Hz,1H),9.06(t,J=6.3H z,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.35(d,J=8.1Hz,1H),7.33– 7.28(m,1H),6.98(dd,J=8.1,1.5Hz,1H),6.16(dd,J=2.1,0.9Hz,1H),4.55(d,J=6.3Hz ,2H),4.13(s,3H),3.56(s,2H),3.09(s,4H),2.01(t,J=7.6Hz,4H),1.79–1.68(m,2H). ESI-MS m / z:415.0[M+H] + .

[0578] Example 66: Synthesis of N-((2-((6-fluoro-2-azaspiro[3.3]hept-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 66)

[0579]

[0580] Compound 66, a white solid, was prepared from intermediate 3-2 and 6-fluoro-2-azaspiro[3.3]heptane trifluoroacetate using the method described in Compound 3.

[0581] 1 H NMR (500MHz, DMSO-d6) δ10.90(d,J=2.0Hz,1H),9.42(d,J=1.2Hz,1H),9.06(t,J=6.3Hz,1H),8. 45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.3Hz,1H),7.36(d,J=8.1Hz,1H),7.33–7.27(m,1H),6.98 (dd,J=8.1,1.5Hz,1H),6.17(dd,J=2.0,1.0Hz,1H),4.91(dp,J=56.0,6.7Hz,1H),4.55(d,J=6. 3Hz, 2H), 4.13 (s, 3H), 3.57 (s, 2H), 3.12 (d, J = 9.1Hz, 4H), 2.49–2.41 (m, 2H), 2.25–2.12 (m, 2H). ESI-MS m / z:433.1[M+H] + .

[0582] Example 67: Synthesis of N-((2-((6,6-difluoro-2-azaspiro[3.3]hept-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 67)

[0583]

[0584] Compound 67, a white solid, was prepared from intermediate 3-2 and 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate using the method described in Compound 3.

[0585] 1H NMR(500MHz,DMSO-d6)δ10.92(d,J=2.1Hz,1H),9.42(s,1H),9.06(t,J=6.3Hz ,1H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.1,1.2Hz,1H),7.36(d,J=8.1Hz,1H) ,7.31(s,1H),6.98(dd,J=8.1,1.5Hz,1H),6.18(dd,J=2.1,1.0Hz,1H),4.55(d ,J=6.3Hz,2H),4.13(s,3H),3.61(s,2H),3.21(s,4H),2.67(t,J=12.6Hz,4H). ESI-MS m / z: 451.0 [M+H] + .

[0586] Example 68: Synthesis of N-((2-((2-azaspiro[3.5]non-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 68)

[0587]

[0588] Compound 68, a white solid, was prepared from intermediates 3-2 and 2-azaspiro[3.5]nonane hydrochloride using the method described in Compound 3.

[0589] 1 H NMR(500MHz,DMSO-d6)δ10.85–10.76(m,1H),9.43(d,J=1.2Hz,1H),8.96(t,J=6.3Hz, 1H),8.45(d,J=6.0Hz,1H),7.74(dd,J=6.1,1.3Hz,1H),7.36(d,J=8.1Hz,1H),7.33–7 .30(m,1H),6.98(dd,J=8.1,1.5Hz,1H),6.18(dd,J=2.0,1.0Hz,1H),4.56(d,J=6.2Hz ,2H),4.13(s,3H),3.63(s,2H),2.90(s,4H),1.54(t,J=5.4Hz,4H),1.39–1.27(m,6H). ESI-MS m / z:443.0[M+H] + .

[0590] Example 69: Synthesis of N-((2-((cyclobutylmethyl)amino)methyl)-1-methyl-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 69)

[0591]

[0592] Compound 69, a white solid, was prepared using the method described in Compound 3, with intermediates B2 and B1.

[0593] 1 H NMR (600MHz, DMSO-d6) δ9.42(d,J=1.2Hz,1H),9.06(t,J=6.3Hz,1H),8.45(d,J=6.0Hz,1H),7. 76(dd,J=6.1,1.2Hz,1H),7.40(d,J=8.1Hz,1H),7.37(s,1H),7.04(dd,J=8.1,1.4Hz,1H),6.27 (s,1H),4.60(d,J=6.3Hz,2H),4.13(s,3H),3.82(s,2H),3.70(s,3H),3.33(s,1H),2.55(d,J= 7.1Hz,2H),2.40(hept,J=7.6Hz,1H),2.00–1.94(m,2H),1.84–1.74(m,2H),1.65–1.57(m,2H). ESI-MS m / z:417.0[M+H] + .

[0594] Example 70: Synthesis of N-((2-((cyclobutylmethyl)amino)methyl)-1H-benzo[d]imidazol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 70)

[0595]

[0596] Step a: Synthesis of intermediate 70-1

[0597] Boc-glycine (1.3 g, 7.5 mmol), EDCI (1.7 g, 9.01 mmol), and HOBT (1.4 g, 10.51 mmol) were dissolved in DCM (50 mL), followed by the addition of a DMF (2 mL) solution of 3,4-diaminobenzonitrile (1.0 g, 7.51 mmol). The mixture was stirred overnight at room temperature. TLC analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure, diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (2.0 g, 91% yield). No purification was required; the crude product was used directly in the next reaction. ESI-MS m / z: 290.9 [M+H] + .

[0598] Step b: Synthesis of intermediate 70-2

[0599] Intermediate 70-1 (2.0 g, 6.83 mmol) was dissolved in acetic acid (10 mL), and the reaction mixture was heated to 70 °C and stirred for 3 hours. TLC showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain a light gray solid (1.5 g, yield 80%).

[0600] 1 H NMR (400MHz, Chloroform-d) δ7.90 (s, 1H), 7.58 (s, 1H), 7.49 (dd, J = 8.3, 1.5Hz, 1H), 5.97 (t, J = 6.1Hz, 1H), 4.55 (d, J = 6.1Hz, 2H), 1.45 (s, 9H). ESI-MS m / z:272.9[M+H] + .

[0601] Step c: Synthesis of intermediate 70-3

[0602] Following the synthetic method for intermediate B1, intermediate B1-2 was replaced with intermediate 70-2 to obtain intermediate 70-3. No purification was required; it was used directly in the next reaction.

[0603] Step d: Synthesis of intermediate 70-4

[0604] Following the synthesis method of intermediate 3-1, intermediate B1 was replaced with intermediate 70-3 to obtain yellow foamy solid intermediate 70-4.

[0605] 1 H NMR(400MHz,Chloroform-d)δ9.64(d,J=1.2Hz,1H),8.44(d,J=6.1Hz,1H),7.53–7.44(m,2H),7.42(t,J=5.9H z,1H),7.26–7.19(m,2H),5.95(s,1H),4.73(d,J=5.9Hz,2H),4.50(d,J=6.0Hz,2H),4.01(s,3H),1.41(s,9H). ESI-MS m / z:436.2[M+H] + .

[0606] Step e: Synthesis of intermediate 70-5

[0607] Following the synthesis method of intermediate A2-2, intermediate 70-5 was obtained from intermediate 70-4.

[0608] ESI-MS m / z: 335.9 [M+H] + .

[0609] Step f: Synthesis of compound 70

[0610] Intermediate 70-5 (50.0 mg, 134.84 μmol) was dissolved in ethanol (6 mL), and DIEA (70.5 μL, 404.51 μmol) and cyclobutylcarboxaldehyde (11.3 mg, 134.84 μmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was then cooled to 0 °C, and NaBH4 (5.1 mg, 134.84 μmol) was added. The mixture was then stirred for another hour at room temperature. TLC analysis confirmed complete consumption of the starting material. The solution was diluted with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified to give compound 3-57 (25.0 mg, 46% yield) as a white solid.

[0611] 1 H NMR(500MHz,Methanol-d4)δ9.47(d,J=1.2Hz,1H),8.40(d,J=6.2Hz,1H),7.67(d d,J=6.2,1.2Hz,1H),7.63–7.58(m,1H),7.53–7.49(m,1H),7.31(dd,J=8.3,1.6Hz ,1H),4.74(s,2H),4.16(s,3H),3.98(s,2H),2.66(d,J=7.3Hz,2H),2.56–2.43(m ,1H),2.11–2.03(m,2H),1.96–1.86(m,1H),1.86–1.77(m,1H),1.74–1.63(m,2H). ESI-MS m / z: 404.0 [M+H] + .

[0612] Example 75: Synthesis of N-((6-((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 75)

[0613]

[0614] Step a: Synthesis of intermediate 75-1

[0615] 6-Chloronicotinaldehyde (1.0 g, 7.06 mmol) was dissolved in DCE, and cyclobutylmethylamine (1.2 g, 14.13 mmol) and acetic acid (0.2 mL) were added separately. The mixture was stirred at room temperature for 2 hours, followed by the addition of STAB in portions, and stirring was continued at room temperature for another 2 hours. TLC was used to determine complete consumption of the starting material. The mixture was quenched with saturated sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain a pale yellow oily liquid (1.0 g, 67% yield).

[0616] 1 H NMR(400MHz,Chloroform-d)δ8.32(d,J=2.4Hz,1H),7.65(dd,J=8.2,2.5Hz,1H),7.28(d,J=8.2Hz,1H),3.76( s,2H),2.62(d,J=7.2Hz,2H),2.46(p,J=7.6Hz,1H),2.10–2.00(m,2H),1.97–1.79(m,2H),1.71–1.58(m,2H). ESI-MS m / z:210.8,212.8[M+H] + .

[0617] Step b: Synthesis of intermediate 75-2

[0618] Intermediate 75-1 (1.0 g, 4.84 mmol) was dissolved in THF, and TEA (1.7 mL, 12.11 mmol) and tert-butyl dicarbonate (2.1 g, 9.68 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. TLC was used to monitor complete consumption of the starting material. The solution was diluted with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give a colorless oily liquid (1.4 g, 92% yield).

[0619] 1 H NMR(400MHz,Chloroform-d)δ8.23(d,J=2.4Hz,1H),7.53(s,1H),7.27(d,J=8.5Hz,1H),4.37(s,2H ), 3.24 (d, J = 37.7Hz, 2H), 2.47 (s, 1H), 2.03–1.89 (m, 2H), 1.88–1.75 (m, 2H), 1.66 (t, J = 9.2Hz, 2H). ESI-MS m / z:310.9,313.0[M+H] + .

[0620] Step c: Synthesis of intermediate 75-3

[0621] Pd₂(dba)₃ (408.2 mg, 445.72 μmol) and Xphos (425.0 mg, 891.44 μmol) were placed in a Schlenk flask, purged with argon three times, and then THF (20 mL), a THF solution of intermediate 75-2 (1.4 g, 4.46 mmol), and LiHMDS (1.0 min THF, 6.7 mL) were added sequentially at room temperature. The reaction mixture was heated to 70 °C and stirred for 3 hours. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 1) to obtain a yellow oily liquid (1.2 g, 92% yield). ESI-MS m / z: 291.9 [M+H] + .

[0622] Step d: Synthesis of intermediate 75-4

[0623] Intermediate 75-3 (1.3 g, 4.41 mmol) was dissolved in DME, and 1,3-dichloropropanone was added. The mixture was heated to 80 °C and stirred overnight. TLC analysis confirmed complete consumption of the starting material. The solution was neutralized with saturated sodium bicarbonate, extracted with EA, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to give a yellow oily liquid (786.8 mg, 49% yield). ESI-MS m / z: 364.0, 366.0 [M+H] + .

[0624] Step e: Synthesis of intermediate 75-5

[0625] Intermediate 75-4 (786.8 mg, 2.16 mmol) was dissolved in dioxane (14 mL), and ammonia (14 mL) was added. The tube was then sealed and stirred at 80 °C for 3 hours. TLC analysis confirmed complete consumption of the starting material. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain a yellow oily liquid (551.1 mg, yield 74%). ESI-MS m / z: 345.0 [M+H] + .

[0626] Step f: Synthesis of intermediate 75-6

[0627] Following the synthesis method of intermediate 3-1, intermediate A2 and intermediate 75-5 were used to obtain brown solid intermediate 75-6. ESI-MS m / z: 504.0 [M+H] + .

[0628] Step g: Synthesis of compound 75-

[0629] Following the synthetic method of intermediate A2-2, white solid compound 75 was obtained from intermediate 75-6.

[0630] 1 H NMR(500MHz,Methanol-d4)δ9.45(d,J=1.2Hz,1H),8.39(d,J=6.2Hz,1H),8.29(dd,J=1.8,1.0 Hz,1H),7.78–7.73(m,1H),7.66(dd,J=6.2,1.2Hz,1H),7.45(dt,J=9.2,0.8Hz,1H),7.32(dd, J=9.3,1.7Hz,1H),4.78–4.73(m,2H),4.16(s,3H),3.73–3.69(m,2H),2.60(d,J=7.3Hz,2H),2 .55–2.45(m,1H),2.11–2.03(m,2H),1.96–1.86(m,1H),1.86–1.77(m,1H),1.72–1.63(m,2H). ESI-MS m / z:404.1[M+H] + .

[0631] Example 79: Synthesis of N-((6-((cyclopentylamino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-carboxamide (Compound 79)

[0632]

[0633] Using the method described in Compound 3, cyclobutylmethylamine was replaced with cyclopentylamine to prepare a white solid compound 79.

[0634] 1 H NMR(600MHz, Methanol-d4)δ9.43(d,J=1.2Hz,1H),8.37(d,J=6.2Hz,1H),8.32–8.2 6(m,1H),7.78–7.73(m,1H),7.63(dd,J=6.2,1.2Hz,1H),7.43(d,J=9.3Hz,1H),7.31 (dd,J=9.3,1.7Hz,1H),4.79–4.72(m,2H),4.14(s,3H),3.70(s,2H),3.05(p,J=7.1 Hz,1H),1.92–1.85(m,2H),1.73–1.65(m,2H),1.59–1.49(m,2H),1.42–1.34(m,2H). ESI-MS m / z:404.1[M+H] + .

[0635] Example 80: Synthesis of N-((2-((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-5-fluoro-1-methyl-1H-indazole-3-carboxamide (Compound 80)

[0636]

[0637] Compound 80, a white solid, was prepared from 5-fluoro-1-methyl-1H-indazole-3-carboxylic acid using the method described in Compound 1.

[0638] 1 H NMR(500MHz, Methanol-d4)δ7.87–7.79(m,1H),7.57(dd,J=9.1,4.1Hz,1H),7.44(d,J=8.1 Hz,1H),7.37–7.34(m,1H),7.24(td,J=9.1,2.5Hz,1H),7.04(dd,J=8.1,1.5Hz,1H),6.30( d,J=0.9Hz,1H),4.67(s,2H),4.08(s,3H),3.85(s,2H),2.61(d,J=7.3Hz,2H),2.49(hept, J=7.7Hz,1H),2.11–2.02(m,2H),1.95–1.85(m,1H),1.85–1.76(m,1H),1.71–1.61(m,2H). ESI-MS m / z:420.2[M+H] + .

[0639] Example 81: Synthesis of N-((2-(((2-fluoro-2-methylpropyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 81)

[0640]

[0641] Compound 81, a white solid, was prepared from intermediate 3-2 and 2-fluoro-2-methylprop-1-amine hydrochloride using the method described in Compound 3.

[0642] 1H NMR (800MHz, Methanol-d4) δ9.48–9.42(m,1H),8.37(d,J=6.2Hz,1H),7.62(dd,J=6.2,1.3Hz,1H),7.43(d,J=8.2Hz,1H),7.39–7.34(m,1H) ,7.05(dd,J=8.1,1.6Hz,1H),6.29(d,J=0.9Hz,1H),4.69(s,2H),4.12(s,3H),3.91(s,2H),2.69(d,J=19.8Hz,2H),1.33(d,J=21.3Hz,6H). ESI-MS m / z:409.1[M+H] + .

[0643] Example 82: Synthesis of N-((2-(((3,3-difluorocyclopentyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 82)

[0644]

[0645] Compound 82, a white solid, was prepared from intermediates 3-2 and 3,3-difluorocyclopentanamine hydrochloride using the method described in Compound 3.

[0646] 1 H NMR (800MHz, Methanol-d4) δ9.46(d,J=1.2Hz,1H),8.38(d,J=6.2Hz,1H),7.63(dd,J=6.1,1.2H z,1H),7.44(d,J=8.1Hz,1H),7.41–7.36(m,1H),7.05(dd,J=8.2,1.5Hz,1H),6.32(d,J=1.0Hz, 1H),4.70(s,2H),4.12(s,3H),3.87(d,J=0.8Hz,2H),3.26(p,J=7.7Hz,1H),2.42–2.31(m,1H), 2.25–2.14(m,1H),2.09–2.02(m,1H),2.01–1.93(m,1H),1.93–1.80(m,1H),1.66–1.57(m,1H). ESI-MS m / z:439.1[M+H] + .

[0647] Example 83: Synthesis of N-((2-((3-fluoropyrrolidone-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 83)

[0648]

[0649] Compound 83, a white solid, was prepared from intermediates 3-2 and 3-fluoropyrrolidine hydrochloride using the method described in Compound 3.

[0650] 1 H NMR (600MHz, DMSO-d6) δ10.99(d,J=2.1Hz,1H),9.42(d,J=1.3Hz,1H),9.08(t,J=6.3Hz,1H),8.45(d,J =6.0Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.38(d,J=8.1Hz,1H),7.33(s,1H),6.99(dd,J=8.1,1.5Hz,1H ),6.27–6.19(m,1H),5.18(dtd,J=55.9,5.0,1.8Hz,1H),4.55(d,J=6.3Hz,2H),4.13(s,3H),3.74–3.66 (m,2H),2.83–2.74(m,2H),2.66–2.56(m,1H),2.39–2.30(m,1H),2.21–2.06(m,1H),1.91–1.77(m,1H). ESI-MS m / z:407.1[M+H] + .

[0651] Example 84: Synthesis of N-((2-((3,3-difluoropyrrolidone-1-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 84)

[0652]

[0653] Compound 84, a white solid, was prepared from intermediates 3-2 and 3,3-difluoropyrrolidine hydrochloride using the method described in Compound 3.

[0654] 1H NMR (600MHz, DMSO-d6) δ11.07–10.97(m,1H),9.42(d,J=1.3Hz,1H),9.09(t,J=6.3Hz,1 H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.0,1.3Hz,1H),7.39(d,J=8.1Hz,1H),7.33(s,1H ),7.00(dd,J=8.1,1.5Hz,1H),6.26–6.21(m,1H),4.56(d,J=6.2Hz,2H),4.14(s,3H),3 .73(s,2H),2.88(t,J=13.3Hz,2H),2.70(t,J=7.0Hz,2H),2.23(tt,J=14.9,7.0Hz,2H). ESI-MS m / z:425.1[M+H] + .

[0655] Example 85: Synthesis of N-((2-((((1-fluorocyclopropyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 85)

[0656]

[0657] Compound 85, a white solid, was prepared from intermediate 3-2 and (1-fluorocyclopropyl)methylamine hydrochloride using the method described in Compound 3.

[0658] 1 H NMR (800MHz, DMSO-d6) δ10.88(d,J=2.1Hz,1H),9.42(d,J=1.3Hz,1H),9.06(t,J=6.3Hz,1 H),8.45(d,J=6.0Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.32(s,1H), 6.98(dd,J=8.1,1.5Hz,1H),6.22(dd,J=2.1,1.0Hz,1H),4.56(d,J=6.3Hz,2H),4.13(s,3H ),3.88(s,2H),2.85(d,J=20.9Hz,2H),2.41(s,1H),0.97–0.89(m,2H),0.67–0.62(m,2H). ESI-MS m / z:407.1[M+H] + .

[0659] Example 86: Synthesis of N-((2-((((1-fluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 86)

[0660]

[0661] Compound 86, a white solid, was prepared from intermediate 3-2 and (1-fluorocyclobutyl)methylamine hydrochloride using the method described in Compound 3.

[0662] 1 H NMR(800MHz,DMSO-d6)δ10.90–10.84(m,1H),9.42(d,J=1.3Hz,1H),9.07(t,J=6.3Hz,1H),8 .45(d,J=6.0Hz,1H),7.76(dd,J=6.0,1.2Hz,1H),7.37(d,J=8.1Hz,1H),7.33(s,1H),6.99( dd,J=8.1,1.5Hz,1H),6.22(dd,J=2.0,1.0Hz,1H),4.57(s,2H),4.13(s,3H),3.85(s,2H),2 .72(d,J=24.2Hz,2H),2.21(s,1H),2.16–2.10(m,4H),1.76–1.68(m,1H),1.42–1.34(m,1H). ESI-MS m / z:421.1[M+H] + .

[0663] Example 87: Synthesis of N-((2-((((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 87)

[0664]

[0665] Compound 87, a white solid, was prepared from intermediate A18 using the method described in Compound 1.

[0666] H NMR (800MHz, DMSO-d6) δ10.90–10.80(m,1H),9.29(d,J=1.2Hz,1H),9.00(t,J=6.3Hz,1H),7.57(t,J=1 .1Hz,1H),7.36(d,J=8.1Hz,1H),7.34–7.30(m,1H),6.98(dd,J=8.1,1.5Hz,1H),6.19(dd,J=2.0,1.0H z,1H),4.55(d,J=6.3Hz,2H),4.07(s,3H),3.77(s,2H),2.60(s,3H),2.51–2.50(m,2H),2.39(dq,J=15 .1,7.4Hz,1H),1.99–1.93(m,2H),1.81(dq,J=11.0,8.5Hz,1H),1.78–1.72(m,1H),1.64–1.57(m,2H). ESI-MS m / z:417.2[M+H] + .

[0667] Example 88: Synthesis of N-((2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 88)

[0668]

[0669] Using the method described in compound 24, cyclobutylmethylamine was replaced with (3-fluorobicyclo[1.1.1]pentan-1-yl)methylamine hydrochloride to prepare a white solid compound 88.

[0670] 1 H NMR (800MHz, DMSO-d6) δ10.84(d,J=2.3Hz,1H),9.28(s,1H),8.99(t,J=6.3Hz,1H),8.16(s,1H),7.36(d,J=8.1Hz,1H),7.32(s,1H),6.98(dd ,J=8.2,1.4Hz,1H),6.20(d,J=1.9Hz,1H),4.55(d,J=6.3Hz,2H),4.32(s,3H),3.80(s,2H),2.74(s,2H),2.71(s,3H),1.92(d,J=2.7Hz,6H). ESI-MS m / z:447.1[M+H] + .

[0671] Example 89: Synthesis of N-((2-((isobutylamino)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 89)

[0672]

[0673] Using the method described in compound 24, cyclobutylmethylamine was replaced with isobutylamine to prepare a white solid compound 89.

[0674] 1 H NMR(800MHz,DMSO-d6)δ10.82(s,1H),9.27(s,1H),8.98(t,J=6.3Hz,1H),8 .15(s,1H),7.35(d,J=8.1Hz,1H),7.31(s,1H),6.97(d,J=8.1Hz,1H),6.18 (d,J=2.0Hz,1H),4.54(d,J=6.2Hz,2H),4.30(s,3H),3.76(s,2H),2.70(s, 3H), 2.28 (d, J = 6.7Hz, 2H), 1.64 (hept, J = 6.7Hz, 1H), 0.83 (d, J = 6.7Hz, 6H). ESI-MS m / z:405.1[M+H] + .

[0675] Example 90: Synthesis of N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 90)

[0676]

[0677] Using the method described in Compound 24, cyclobutylmethylamine was replaced with (3,3-difluorocyclobutyl)methylamine hydrochloride to prepare a white solid compound 90.

[0678] 1H NMR (800MHz, DMSO-d6) δ10.84(d,J=2.2Hz,1H),9.28(s,1H),8.99(t,J=6.3Hz,1 H),8.16(d,J=1.3Hz,1H),7.36(d,J=8.1Hz,1H),7.32(s,1H),6.98(dd,J=8.1,1. 5Hz,1H),6.21(d,J=2.0Hz,1H),4.55(d,J=6.3Hz,2H),4.32(s,3H),3.79(s,2H) ,2.71(s,3H),2.57(d,J=7.1Hz,4H),2.24(dddt,J=27.4,13.2,10.0,6.8Hz,3H). ESI-MS m / z: 453.0 [M+H] + .

[0679] Example 91: Synthesis of N-((2-((cyclopentylamino)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 91)

[0680]

[0681] Using the method described in compound 24, cyclobutylmethylamine was replaced with cyclopentylamine to prepare a white solid compound 91.

[0682] 1 H NMR (500MHz, DMSO-d6) δ10.89–10.78(m,1H),9.28(s,1H),8.98(t,J=6.3Hz,1H),8.16(d,J=1.2H z,1H),7.35(d,J=8.1Hz,1H),7.32(d,J=1.4Hz,1H),6.97(dd,J=8.1,1.5Hz,1H),6.20(dd,J=2.0, 1.0Hz,1H),4.55(d,J=6.2Hz,2H),4.32(s,3H),3.77(s,2H),2.97(p,J=6.3Hz,1H),2.71(s,3H),1 .68(dtdd,J=12.1,6.7,5.2,1.5Hz,2H),1.63–1.54(m,2H),1.49–1.39(m,2H),1.35–1.26(m,2H). ESI-MS m / z:417.0[M+H] + .

[0683] Example 92: Synthesis of N-((2-((6-azaspiro[2.5]octane-6-yl)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 92)

[0684]

[0685] Using the method described in compound 24, cyclobutylmethylamine was replaced with 6-azaspiro[2.5]octane hydrochloride to prepare a white solid compound 92.

[0686] 1 H NMR (500MHz, DMSO-d6) δ10.92(d,J=2.2Hz,1H),9.28(s,1H),8.99(t,J=6.3Hz,1H),8.17(d,J=1.2Hz,1H),7.37(d,J=8.1Hz,1H),7.33(s,1H),6.98 (dd,J=8.1,1.5Hz,1H),6.21(d,J=1.9Hz,1H),4.55(d,J=6.2Hz,2H),4.32 (s,3H),3.59(s,2H),2.72(s,3H),2.40(s,4H),1.32(s,4H),0.21(s,4H). ESI-MS m / z:442.9[M+H] + .

[0687] Example 93: Synthesis of N-((2-((6-azaspiro[3,4]octane-6-yl)methyl)-1H-indol-6-yl)methyl)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 93)

[0688]

[0689] Using the method described in compound 24, cyclobutylmethylamine was replaced with 6-azaspiro[3.4]octane hydrochloride to prepare white solid compound 93.

[0690] 1H NMR (600MHz, DMSO-d6) δ10.91(d,J=2.2Hz,1H),9.27(s,1H),8.98(t,J=6.3Hz,1H),8.15(d, J=1.2Hz,1H),7.35(d,J=8.1Hz,1H),7.34–7.27(m,1H),6.97(dd,J=8.1,1.5Hz,1H),6.18(dd ,J=2.1,0.9Hz,1H),4.53(d,J=6.3Hz,2H),4.30(s,3H),3.62(s,2H),2.70(t,J=0.8Hz,3H), 2.51(s,2H),2.48–2.46(m,2H),1.94–1.83(m,4H),1.79(t,J=7.0Hz,2H),1.76–1.63(m,2H). ESI-MS m / z:443.1[M+H] + .

[0691] Example 94: Synthesis of N-((2-((2-azaspiro[4.4]non-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 94)

[0692]

[0693] Compound 94, a white solid, was prepared from intermediates 3-2 and 2-azaspiro[4.4]nonane using the method described in Compound 3.

[0694] 1 H NMR(500MHz,DMSO-d6)δ10.95–10.83(m,1H),9.42(d,J=1.2Hz,1H),9.06(t,J=6.2Hz,1H),8 .45(d,J=6.1Hz,1H),7.76(dd,J=6.1,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.35–7.29(m,1H), 6.98(dd,J=8.1,1.5Hz,1H),6.19(dd,J=1.9,1.0Hz,1H),4.56(d,J=6.3Hz,2H),4.13(s,3H) ,3.65(s,2H),2.55(t,J=7.0Hz,2H),2.37(s,2H),1.62(t,J=7.0Hz,2H),1.57–1.42(m,8H). ESI-MS m / z:443.1[M+H] + .

[0695] Example 95: Synthesis of N-((2-((2-azaspiro[4.5]dec-2-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 95)

[0696]

[0697] Compound 95, a white solid, was prepared from intermediates 3-2 and 2-azaspiro[4.5]decane using the method described in Compound 3.

[0698] 1 H NMR (500MHz, DMSO-d6) δ10.88(d,J=2.0Hz,1H),9.43(d,J=1.2Hz,1H),9.05(t,J=6.3Hz,1 H),8.45(d,J=6.0Hz,1H),7.75(dd,J=6.1,1.3Hz,1H),7.37(d,J=8.1Hz,1H),7.33(s,1H), 6.99(dd,J=8.1,1.5Hz,1H),6.19(dd,J=2.0,1.0Hz,1H),4.56(d,J=6.3Hz,2H),4.13(s,3H ),3.62(s,2H),2.50–2.48(m,2H),2.29(s,2H),1.49(t,J=6.9Hz,2H),1.42–1.26(m,10H). ESI-MS m / z:457.0[M+H] + .

[0699] Example 96: Synthesis of N-((2-((7-azaspiro[3.5]non-7-yl)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 96)

[0700]

[0701] Compound 96, a white solid, was prepared from intermediates 3-2 and 7-azaspiro[3.5]nonane hydrochloride using the method described in Compound 3.

[0702] 1H NMR(500MHz,DMSO-d6)δ10.88(d,J=1.9Hz,1H),9.43(s,1H),9.05(t,J=6.3Hz,1H),8.4 5(d,J=6.0Hz,1H),7.75(dd,J=6.1,1.2Hz,1H),7.36(d,J=8.1Hz,1H),7.33(s,1H),6.9 8(dd,J=8.1,1.5Hz,1H),6.19(d,J=2.0Hz,1H),4.55(d,J=6.2Hz,2H),4.13(s,3H),3.5 0(s,2H),2.25(s,4H),1.86–1.74(m,2H),1.66(t,J=7.6Hz,4H),1.51(t,J=5.4Hz,4H). ESI-MS m / z:443.1[M+H] + .

[0703] Example 97: N-((2-(((cyclobutylmethyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 97)

[0704]

[0705] Compound 97, a white solid, was prepared from intermediates A2 and B3 using the method described in Compound 3. ESI-MS m / z: 421.1 [M+H] + .

[0706] Example 99: N-((6-(((cyclobutylmethyl)amino)methyl)-1-methoxyisoquinoline-3-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 99)

[0707]

[0708] Compound 99, a white solid, was prepared from intermediates A2 and B4 using the method described in Compound 3. ESI-MS m / z: 445.1 [M+H] + .

[0709] Example 100: N-((6-(((cyclobutylmethyl)amino)methyl)-1-methylisoquinoline-3-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 100)

[0710]

[0711] Compound 100, a white solid, was prepared from intermediates A2 and B5 using the method described in Compound 3. ESI-MS m / z: 429.1 [M+H] + .

[0712] Example 108: 7-Bromo-N-((2-((((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 108)

[0713]

[0714] Compound 108, a white solid, was prepared from intermediates A19 and B1 using the method described in Compound 3. ESI-MS m / z: 481.3 [M+H] + .

[0715] Example 110: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-7-(methylamino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 110)

[0716]

[0717] A yellow, oily liquid intermediate 110-1 was prepared from intermediates A20 and B1 using the method described in Compound 3. ESI-MS m / z: 582.1 [M+H] + .

[0718] Intermediate 110-1 (95.0 mg, 163.31 μmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 3 hours. TLC analysis confirmed complete consumption of the starting material. The reaction solution was concentrated under reduced pressure, neutralized with saturated sodium bicarbonate solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by pre-HPLC to obtain a white solid compound 110 (32.0 mg, 45% yield). ESI-MS m / z: 432.1 [M+H] + .

[0719] Example 115: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-methyl-7-(methyl-d3)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 115)

[0720]

[0721] Compound 115, a white solid, was prepared from intermediates A21 and B1 using the method described in Compound 3. ESI-MS m / z: 420.1 [M+H] + .

[0722] Example 116: N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1,7-bis(methyl-d3)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 116)

[0723]

[0724] Compound 116, a white solid, was prepared by replacing iodomethane with deuterated iodomethane using the method described in compound 115. ESI-MS m / z: 423.1 [M+H] + .

[0725] Biological evaluation

[0726] METTL3 enzyme activity assay

[0727] This experiment used HTRF (High-Temperature Hydrofluoric Ratio) to detect the activity of the compounds. HTRF technology includes two techniques: fluorescence resonance energy transfer and time-resolved fluorescence. 3+ The labeled antibody (HTRF donor) recognizes the affinity tag, and the glutathione S-transferase (GST) recognizes the corresponding labeled protein. Biotinylated RNA is labeled with biotin-streptomycin, and the corresponding labeled RNA is recognized through the interaction between biotin-streptomycin and XL665-conjugated streptomycin. When biomolecules interact, fluorescence resonance energy transfer occurs between the acceptor and donor, with two excitation wavelengths at 620 nm and 665 nm. Without interaction, only the 620 nm excitation wavelength is present. In this experiment, the GST-tagged YTHDF2 protein specifically recognizes biotinylated methylated single-stranded RNA fragments, generating a 665 nm light signal. The intensity of the light signal is correlated with the degree of RNA methylation. The methyltransferase METTL3 methylates substrate RNA fragments; the inhibitory effect of compounds on METTL3 activity can be achieved by detecting the degree of RNA methylation, thus reflecting the inhibitory effect of the compounds on METTL3.

[0728] 1.1 Reagents and Instruments

[0729] Instruments and equipment: Tecan Spark Cyto multi-functional microplate reader, TopSeal TM -A films (item number 6005185), White optiplate TM -384 (item number 6007299);

[0730] Reagent: HTRF donor Eu 3+ The labeled antibody and HTRF acceptor XL665-conjugated streptavidin were purchased from PerkinElmer (Shanghai); the enzyme reaction substrate 5′-biotinylated singlestrand(ss)RNA (5′-AAGAACCGGACUAAGCU-3′) was purchased from Guangzhou Ruibo Biotechnology Co., Ltd.; the recombinant METTL3 / METTL14 complex and recombinant YTHDF2 were purchased from Shanghai Merde Shanghai Biotechnology Center; and the methyl donor SAM (catalog number A7007) was purchased from Sigma-Aldrich (USA).

[0731] 1.2 Test Methods

[0732] (1) Prepare a reaction buffer and use the reaction buffer to dilute the METTL3 / METTL14 enzyme, SAM, inhibitors and RNA fragments;

[0733] (2) Add the following reagents to the 384 microplate white plate in sequence: 5 μL of inhibitor (4×) or AssayBuffer, 5 μL of METTL3 / METTL14 enzyme (4×), incubate at room temperature for 20 min, and then add the following reagents in sequence: 5 μL of RNA fragment (4×), 5 μL of SAM (4×);

[0734] (3) Seal the microplate in the dark and let it stand at room temperature for 60 minutes;

[0735] (4) Prepare Detection Buffer. Use Detection Buffer to prepare SA-XL665 Beads and YTHDF2 enzyme. Add 10 μL of (4×)SA-XL665 Beads and 10 μL of (4×)YTHDF2 enzyme, seal and incubate in the dark for 60 min.

[0736] (5) Read the values ​​using a Tecan multi-functional microplate reader. Two sets of wells were set up for each experiment, and a blank control group was also set up.

[0737] Inhibition rate (%) = {[(Positive control signal value - Blank control signal value) - (Test compound signal value - Blank control signal value)] / (Positive control signal value - Blank control signal value)}

[0738] Using inhibition rate (%) as the ordinate and compound concentration as the abscissa, competitive inhibition curves were plotted using Graphpad Prism software. The IC50 of the compounds was then calculated using the resulting regression equations. 50 .

[0739] IC50 of the compounds in the examples for METTL3 enzymatic inhibition 50 The values ​​are shown in Table 2.

[0740] Table 2

[0741]

[0742]

[0743] Note: "+" indicates 1.0μM≤IC 50 ≤10μM; "++" indicates 0.2μM≤IC 50 <1.0μM; "+++" indicates IC 50 <0.2μM.

[0744] Conclusion: As shown in Table 2, the compounds of the present invention have a significant inhibitory effect on the activity of METTL3 enzyme.

[0745] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0746] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A fused bicyclic compound or a pharmaceutically acceptable salt thereof, said fused bicyclic compound having the structural features shown in general formula (I): in, X 1 Independently selected from CR A1 C(R) A1 )2, N, NR A2 , O or S; X 2 Independently selected from CR A1 C(R) A1 2. N or NR A2 ; X 3 Independently selected from C or N; X 4 X 5 X 6 and X 7 Each is independently selected from N or CR A1 ; X 8 and X 9 Each is independently selected from C or N; in, R A1 Independently selected from H, halogen, cyano, nitro, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR A1a -SR A1a -C(=O)R A1a -S(=O)R A1a -S(=O)2R A1a -C(=O)OR A1a -OC(=O)R A1a -NR A1b R A1c -C(=O)NR A1b R A1c -OC(=O)NR A1b R A1c -S(=O)2NR A1b R A1c -NR A1d C(=O)R A1a -NR A1d S(=O)2R A1a , wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, D, halogen, -OH, cyano, nitro, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 cycloalkyl; R A2 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -C(=O)OR A1a -C(=O)NR A1b R A1c or -S(=O)2R A1a , wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each independently substituted by 1 to 3 substituents, said substituents being independently selected from H, D, halogen, -OH, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C l-6 Halogenated alkyl, hydroxylated C l-6 alkyl and cyano substituted C l-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR A2a -SR A2a -C(=O)R A2a -S(=O)R A2a -S(=O)2R A2a -C(=O)OR A2a -OC(=O)R A2a -NR A2b R A2c -C(=O)NR A2b R A2c -OC(=O)NR A2b R A2c -S(=O)2NR A2b R A2c -NR A2d C(=O)R A2a or -NR A2d S(=O)2R A2a ; R A1a R A1b R A1c R A2a R A2b and R A2c Each is independently selected from H, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; Or, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A1b and R A1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group, wherein the 4- to 9-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Haloalkyl, optionally, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group, or R A1b and R A1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 6-membered heterocyclic alkyl group; Or, R A2b and R A2c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A2b and R A2c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group, wherein the 4- to 9-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Haloalkyl, optionally, R A2b and R A2c Together with the N atom attached to it, it forms a 4- to 9-membered heterocyclic alkyl group, or R A2b and R A2c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 9-membered heterocyclic alkyl group; R A1d and R A2d Each is independently selected from H or C 1-3 alkyl; The L mentioned is selected from Or 5 to 6 heteroaryl groups, where L is selected from At that time, it interacts with the carbonyl side The 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, which are independently selected from H, halogens, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy or C 3-8 cycloalkyl; in, R L1 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 Each cycloalkyl group is optionally substituted with 1 to 3 substituents, said substituents being independently selected from halogens, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; The B ring mentioned is selected from C. 6-10 arylene or 5- to 10-membered heteroarylene, wherein the 5- to 10-membered heteroarylene contains 1 to 5 heteroatoms selected from N, O, and S; wherein the cyclic carbon atom of the 5- to 10-membered heteroarylene may optionally be oxidized and substituted to form a carbonyl group; the C 6-10 The arylene or 5- to 6-membered heteroarylene is independently substituted by 1 to 4 substituents, said substituents being independently selected from H, halogen, -OH, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C l-6 Halogenated alkyl, hydroxylated C l-6 alkyl and cyano substituted C l-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR B1a -SR B1a -C(=O)R B1a -S(=O)R B1a -S(=O)2R B1a -C(=O)OR B1a -OC(=O)R B1a -NR B1b R B1c -C(=O)NR B1b R B1c -OC(=O)NR B1b R B1c -S(=O)2NR B1b R B1c -NR B1d C(=O)R B1a or -NR B1d S(=O)2R B1a The 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O, and S; R B1a R B1b and R B1c Each is independently selected from H, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; Or, R B1b and R B1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group, or R B1b and R B1c The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N atoms. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; The R mentioned 1a R 1b R 2a and R 2b Each is independently selected from H, deuterium, halogen, cyano, nitro, hydroxyl, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 4- to 7-membered heterocycloalkyl group are each optionally substituted with 1 to 3 substituents, said substituents being independently selected from H, halogen cyano, nitro, hydroxyl, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy or C 3-6 Cycloalkyl, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; R 1a With R 1b Optionally, it can form carbonyl (=O), thiocarbonyl (=S), or C groups with the atoms it is attached to. 3-6 The cycloalkyl group or heterocyclic group forms a 3- to 6-membered heterocyclic group with another heteroatom selected from O, N, or S, each of which is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; R 2a With R 2b Optionally, it can form carbonyl (=O), thiocarbonyl (=S), or C groups with the atoms it is attached to. 3-6 The cycloalkyl group or heterocyclic group forms a 3- to 6-membered heterocyclic group with another heteroatom selected from O, N, or S, each of which is optionally substituted by 1-3 substituents, the substituents being independently selected from halogens, C, and N. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; The R mentioned 3a and R 3b Each is independently selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl or Wherein, the C 1-6 Alkyl, C 3-8 The cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl groups are each optionally substituted by 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 cycloalkyl; Or, R 3a and R 3b Together with the N atom attached thereto, it forms a 3- to 12-membered heterocyclic alkyl group, or R 3a and R 3b The N atom attached thereto, along with other heteroatoms selected from O, N, or S, forms a 3- to 12-membered heterocyclic alkyl group, wherein the 3- to 12-membered heterocyclic alkyl group is optionally substituted with 1 to 3 substituents, the substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 cycloalkyl; The ring C is selected from phenyl, C 3-12 Cycloalkyl or 3 to 12-membered heterocyclic groups, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S; wherein the phenyl, C 3-12 The cycloalkyl group and the 3- to 12-membered heterocyclic group are each optionally substituted with 1 to 3 substituents, said substituents being independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl and cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl or 4- to 7-membered heterocyclic alkyl groups.

2. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Selected from m is selected from 0, 1, 2, 3 or 4.

3. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R A1 Independently selected from H, halogen, C 1-6 Alkyl, -OR A1a or -NR A1b R A1c R A1a R A1b R A1c Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl, or, R A1b and R A1c Together with the N atom attached thereto, they form 4 to 9-membered heterocyclic alkyl groups, optionally, R A1b and R A1c Together with the N atom attached to it, it forms a 4- to 6-membered heterocyclic alkyl group.

4. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R A2 Independently selected from H or C 1-6 Alkyl; the C 1-6 Each alkyl group is independently substituted by 1 to 3 substituents, which are independently selected from H, D or halogens.

5. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, L is selected from 6. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, Ring B is selected from Ring B passes through *side and R 1a R 1b The carbon atom is substituted and attached; in, n is selected from 0, 1, 2, 3 or 4; R B1 The definition is the same as R A1 .

7. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R 3a and R 3b Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, or Wherein, methyl, ethyl, propyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl are each optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from H, F, Cl, Br, I, -OH, =O, cyano, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, or cyclopropyl. The ring C is selected from substituted or unsubstituted phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, piperidine, morpholine, piperazine, 1,4-diazaheptanyl, cyclopropylcyclopentyl, cyclopentylcyclobutyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylazacyclohexyl, cyclopentylazacyclobutyl, cyclopentylazacyclopentyl, cyclopentylazacyclohexyl alkyl, cyclohexylazocyclobutyl, cyclohexylazocyclopentyl, cyclohexylazocyclohexyl, azacyclobutylazocyclobutyl, azacyclobutylazocyclopentyl, azacyclobutylazocyclohexyl, azacyclopentylazocyclobutyl, azacyclopentylazocyclopentyl, azacyclopentylazocyclohexyl, azacyclohexylazocyclobutyl, azacyclohexylazocyclohexyl Cyclopentyl, azirocyclohexyl, cyclobutylspiroazirocyclobutyl, cyclobutylspiroazirocyclopentyl, cyclobutylspiroazirocyclohexyl, cyclopentylspiroazirocyclobutyl, cyclopentylspiroazirocyclopentyl, cyclopentylspiroazirocyclohexyl, cyclohexylspiroazirocyclobutyl, cyclohexylspiroazirocyclopentyl, cyclohexylspiroazirocyclohexyl, azirocyclobutylspiroazirocyclobutyl, azirocyclobutylspiroazirocyclobutyl Heterocyclic pentyl, azirrocyclic butyl spiroazirrocyclic hexyl, azirrocyclic pentyl spiroazirrocyclic butyl, azirrocyclic pentyl spiroazirrocyclic pentyl, azirrocyclic hexyl spiroazirrocyclic butyl, azirrocyclic hexyl spiroazirrocyclic pentyl, azirrocyclic hexyl spiroazirrocyclic hexyl, oxocyclic butyl, oxocyclic pentyl, oxocyclic hexyl, cyclopropyl azirrocyclic butyl, cyclopropyl azirrocyclic pentyl, cyclopropyl oxacyclohexyl, cyclobutyl oxacyclobutyl, cyclobutyl oxacyclopentyl, cyclobutyl oxacyclohexyl, cyclopentyl oxacyclopentyl, cyclopentyl oxacyclopentyl, cyclopentyl oxacyclohexyl, cyclohexyl oxacyclobutyl, cyclohexyl oxacyclopentyl, cyclohexyl oxacyclohexyl, aziridine oxacyclobutyl, aziridine oxacyclohexyl pentyl, aziridine benzoxycyclohexyl, aziridine pentyl benzoxycyclohexyl, aziridine pentyl benzoxycyclohexyl, aziridine benzoxycyclohexyl, aziridine benzoxycyclohexyl, aziridine benzoxycyclohexyl, aziridine benzoxycyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl Butyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclohexylspirocyclohexyl, azircyclic butylspirocyclohexyl, azircyclic butylspirocyclohexyl, azircyclic butylspirocyclohexyl, azircyclic pentylspirocyclohexyl, azircyclic pentylspirocyclohexyl, azircyclic pentylspirocyclohexylAzahexylspirooxetyl, azahexylspirooxetyl, azahexylspirooxetyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecyl, adamantyl, When substituted, it may be further selected by 1-3 groups chosen from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

8. The fused bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R 3a and R 3b Together with the N atom attached to it, it forms substituted or unsubstituted aziridine, aziridine, piperazine, aziridine-cyclopropyl, aziridine-cyclobutyl, aziridine-cyclopentyl, aziridine-cyclohexyl, aziridine-cyclopentyl, aziridine-cyclopropyl, aziridine-cyclopentyl, aziridine-cyclopentyl, aziridine-cyclopentyl, aziridine-cyclohexyl, aziridine-cyclopropyl, aziridine-cyclobutyl, aziridine-cyclopentyl, aziridine-cyclohexyl, aziridine-aziridine-cyclobutyl, aziridine-aziridine-cyclopentyl, aziridine-aziridine-cyclobutyl, aziridine-aziridine-cyclopentyl, aziridine-aziridine-cyclopentyl, aziridine-cyclopentyl-aziridine, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl, aziridine-cyclopentyl-cyclobutyl Azahexacyclopentyl, azahexacyclopentyl-azahexacyclohexyl, azahexacyclohexyl-azahexacyclobutyl, azahexacyclohexyl-azahexacyclopentyl, azahexacyclohexyl-azahexacyclohexyl, azahexacyclobutylspiroazahexacyclobutyl, azahexacyclobutylspiroazahexacyclopentyl, azahexacyclobutylspiroazahexacyclobutyl, azahexacyclopentylspiroazahexacyclopentyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclopentyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclopentyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl, azahexacyclohexylspiroazahexacyclobutyl When substituted, it may be further selected by 1-3 groups chosen from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyl.

9. A pharmaceutical composition, characterized in that, Includes the fused bicyclic compounds as described in any one of claims 1 to 8, or their pharmaceutically acceptable salts, stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, cocrystals, and Pharmaceutically acceptable carrier.

10. The use of the fused bicyclic compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating and / or preventing diseases associated with or mediated by METTL3 activity; Optionally, the disease is selected from cancer, autoimmune diseases, inflammatory diseases, or autosomal dominant polycystic kidney disease; alternatively, the disease is cancer; further alternatively, the cancer is selected from acute myeloid leukemia, breast cancer, liver cancer, malignant glioma, bladder cancer, stomach cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, osteosarcoma, oral squamous cell carcinoma, thyroid cancer, uveal melanoma, ovarian cancer, head and neck squamous cell carcinoma, skin squamous cell carcinoma, or nasopharyngeal carcinoma; even more alternatively, the cancer is acute myeloid leukemia.

11. The use of the fused bicyclic compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9, and the use of one or more antitumor drugs in the preparation of a medicament for treating and / or preventing cancers associated with or mediated by METTL3 activity; Optionally, the antitumor drug is selected from one or more of alkylating agents, platinum chelating agents, metabolic antagonists, plant alkaloids, hormone anticancer agents, antibody drugs, VEGFR or EGFR inhibitors, mTOR inhibitors, PI3K kinase inhibitors, B-Raf inhibitors, AKT inhibitors, and immune checkpoint inhibitors.

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