Fused bicyclic compound, and preparation method therefor, composition thereof and use thereof

Abstract

The present application relates to a fused bicyclic compound, a pharmaceutically acceptable salt thereof, a preparation method therefor, a composition thereof and the use thereof. The compound, acting as a METTL3 inhibitor, has a structure as shown in the following general formula (I).

Description

Fused bicyclic compounds, preparation methods, compositions and applications thereof

[0001] Related applications

[0002] This application claims priority to the Chinese patent application with the application number 2024113442649 and the title "Fused bicyclic compounds, preparation methods, compositions and applications thereof", filed on September 25, 2024, the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0003] The present application relates to the technical field of medicine, in particular to a fused bicyclic compound, a preparation method, a composition and an application thereof. BACKGROUND

[0004] Among all RNA modifications, N 6 -methyladenine (m 6 A) is the most abundant chemical modification. This modification is distributed in all RNA species, including mRNA, lincRNA, pri-miRNA and rRNA, and plays a key role in physiological functions and disease occurrence by regulating gene expression. 6 A is a dynamic and reversible modification, which is jointly regulated by methylase "writer" (METT3-METTL14, METTL16 and METTL5, etc.), methylase "reader" (YTHDF1-3, YTHDC1 and YTHDC2) and demethylase "eraser" (ALBH5 and FTO). Among them, the METTL3-METTL14 complex is the key methylase for m 6 A modification, METTL3 uses S-adenosyl-L-methionine (SAM) as a methyl donor to provide a methylation catalytic site for the substrate RNA, while METTL14 plays a role in recognizing the substrate and stabilizing the complex. METTL3-METTL14 complex needs the assistance of Wilms' tumor-associated protein (WTAP) to ensure positioning to the correct modification site. METTL3 specifically modifies the target RNA, thereby regulating biological processes such as cell cycle, cell proliferation, differentiation, migration, invasion, apoptosis, metabolism and immune response.

[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 combined 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] wherein,

[0010] X 1 is independently selected from CR A1 , C(R A1 )2, N, NR A2 , O or S;

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

[0012] X 3 is independently selected from C or N;

[0013] X 4 , X 5 , X 6 and X 7 are each independently selected from N or CR A1 ;

[0014] X 8 and X 9 are each independently selected from C or N;

[0015] wherein,

[0016] 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 R A1c , -C(=O)NRA1b 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;

[0017] 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 , -SR A2a , -C(=O)RA2a -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 ;

[0018] R A1a , R A1b , R A1c , R A2a , R A2b and R A2c are each independently selected from H, -NH2, -OH, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl;

[0019] or, R A1b and R A1c together with the N atom to which they are attached form a 4- to 9-membered heterocycloalkyl, or R A1b and R A1c together with the N atom to which they are attached and a further heteroatom selected from O, N, or S form a 4- to 9-membered heterocycloalkyl, wherein said 4- to 9-membered heterocycloalkyl is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl, optionally, R A1b and R A1c together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl, or R A1b and R A1c together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl;

[0020] or, R A2b and R A2c form, together with the N atom to which they are attached, a 4- to 9-membered heterocycloalkyl group, or R A2b and R A2c form, together with the N atom to which they are attached and a further heteroatom selected from O, N or S, a 4- to 9-membered heterocycloalkyl group, wherein said 4- to 9-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, optionally R A2b and R A2c form, together with the N atom to which they are attached, a 4- to 9-membered heterocycloalkyl group, or R A2b and R A2c form, together with the N atom to which they are attached and a further heteroatom selected from O, N or S, a 4- to 9-membered heterocycloalkyl group;

[0021] R A1d and R A2d are each independently selected from H or C 1-3 alkyl;

[0022] said L is selected from or 5- to 6-membered heteroarylene, when L is selected from , it is attached via the carbonyl side to , said 5- to 6-membered heteroarylene is each optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl;

[0023] wherein,

[0024] R L1 is selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl is each optionally substituted with 1-3 substituents independently selected from halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy or C 1-6haloalkyl, hydroxy-substituted C

[0025] said B ring is selected from C 6-10 arylene or 5- to 10-membered heteroarylene, wherein said 5- to 10-membered heteroarylene contains 1 to 5 heteroatoms selected from N, O, S; wherein a ring carbon atom of said 5- to 10-membered heteroarylene is optionally oxidized to form a carbonyl group; said C 6-10 arylene or 5- to 6-membered heteroarylene is independently substituted with 1-4 substituents independently selected from H, halogen, -OH, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C l-6 haloalkyl, hydroxy-substituted 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 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 , said 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O, S;

[0026] R B1a , R B1b and R B1c are each independently selected from H, -NH2, -OH, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl;

[0027] or, R B1b and R B1c form, together with the N atom to which they are attached, a 4- to 6-membered heterocycloalkyl group, or R B1b and R B1c form, together with the N atom to which they are attached and a further heteroatom selected from O, N or S, a 4- to 6-membered heterocycloalkyl group, wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0028] said R 1a , R 1b , R 2a and R 2b are each independently selected from H, deuterium, halogen, cyano, nitro, hydroxyl, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with 1-3 substituents 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, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 3 heteroatoms selected from N, O, S;

[0029] R 1a and R 1b optionally form, together with the atom to which they are attached, a carbonyl (=0), thiocarbonyl (=S), C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl with a further heteroatom selected from O, N or S, said cycloalkyl or heterocyclyl each optionally substituted with 1-3 substituents independently selected from halogen, C 1-4 alkyl or C 1-4 haloalkyl;

[0030] R 2aR 2b optionally with an atom forming a carbonyl (=0), a thiocarbonyl (=S), a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl with another heteroatom selected from O, N or S, each of said cycloalkyl or heterocyclyl being optionally substituted with 1-3 substituents independently selected from halogen, C 1-4 alkyl or C 1-4 haloalkyl;

[0031] said R 3a and R 3b are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl or wherein said C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl;

[0032] or, R 3a and R 3b form together with the N atom to which they are attached a 3- to 12-membered heterocycloalkyl, or R 3a and R 3b form together with the N atom to which they are attached and another heteroatom selected from O, N or S a 3- to 12-membered heterocycloalkyl, wherein said 3- to 12-membered heterocycloalkyl is optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl;

[0033] cycloC is selected from phenyl, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl, said heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 3-12The 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.

[0034] 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

[0035] Pharmaceutically acceptable carrier.

[0036] 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.

[0037] 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. Detailed Implementation

[0038] 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.

[0039] 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.

[0040] As used herein, the terms "and / or", "or / and", "and / or" in an optional sense include any one of two or more associated listed items, as well as any and all combinations of the associated listed items, including a combination of any two of the associated listed items, a combination of any more of the associated listed items, or a combination of all of the associated listed items.

[0041] As used herein, "one or more" means any one, any two, or any two or more of the listed items.

[0042] In the present application, "first aspect", "second aspect", "third aspect", "fourth aspect" and the like are only for the purpose of description, and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth" and the like only serve the purpose of non-exhaustive enumeration and description, and should be understood as not constituting a closed limitation on the quantity.

[0043] In the present application, in the technical features described in an open-ended manner, both a closed technical solution consisting of the listed features and an open technical solution containing the listed features are included.

[0044] In the present application, when referring to a numerical interval, unless otherwise specified, the numerical interval is considered to be continuous and includes the minimum value and the maximum value of the range, as well as every value between the minimum value and the maximum value. Further, when the range refers to integers, every integer between the minimum value and the maximum value of the range is included. In addition, when multiple ranges are provided to describe a feature or a characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges encompassed therein.

[0045] In the present application, the percentage content, unless otherwise specified, refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.

[0046] In the present application, the percentage concentration, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added ingredient in the system after the ingredient is added.

[0047] In the present application, the temperature parameter, unless otherwise specified, allows both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0048] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] The term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon group. Preferably, the alkyl group contains 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, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0050] The term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, 2-propyloxy, butoxy, t-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. Preferably, the alkoxy group has about 1-6 carbon atoms, more preferably about 1-4 carbon atoms.

[0051] The term "haloalkyl" refers to an alkyl group as defined herein substituted with one or more halogen groups as defined herein. Preferably, the haloalkyl group can be a mono-haloalkyl, di-haloalkyl, or poly-haloalkyl group, including a per-haloalkyl group. Mono-haloalkyl groups can have one iodo, bromo, chloro, or fluoro substituent. Di-haloalkyl and poly-haloalkyl groups can be substituted with two or more of the same halogen groups or a combination 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. Per-haloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms. Preferred haloalkyl groups are trifluoromethyl and difluoromethyl.

[0052] The term "alkenyl" refers to an unsaturated branched or straight chain group having at least one double bond. Preferably, the alkenyl 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. Alkenyl groups include, but are not limited to, propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, heptenyl, octenyl, and the like.

[0053] 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. Alkynyl groups include, but are not limited to, propynyl, 1-butyryl, hexynyl, pentynyl, hexynyl, heptynyl, octynyl, and the like.

[0054] The term "cycloalkyl" refers to non-aromatic hydrocarbons containing ring carbon atoms, and can be monocyclic cycloalkyl, or spirocyclic cycloalkyl, or bridged cycloalkyl. Exemplary monocyclic carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. Exemplary bicyclic carbocyclic groups include bornyl, decalinyl, 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 tricyclic carbocyclic groups include adamantyl. Additionally, "cycloalkyl" can also contain one or more double bonds, representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.

[0055] The term "heterocyclyl" refers to at least one carbon atom of a cycloalkyl group is replaced with a non-carbon atom, which can be N, O, S, and wherein N and S can optionally be oxidized to various oxidation states. In one embodiment, the heterocyclyl is a 4- to 7-membered heterocycloalkyl. Examples of heterocyclyl groups include dihydrofuryl, [1,3]dioxolane, 1,4-dioxane, 1,4-dithiane, piperazinyl, 1,3-dioxolane, imidazolidinyl, imidazolinyl, pyrrolidine, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxepinyl, thiomorpholinyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl, and diazepinyl.

[0056] The term "spiro" or "spirocyclic" refers to a polycyclic group in which a substituent or unsubstituent monocyclic ring shares an atom (referred to as a spiro atom) with another ring in the spiro system. The number of ring atoms in a spiro system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings can contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, or S (=O) n

[0057] ​​​​​The term "fused ring" or "fused ring group" means a polycyclic group in which each ring in the system shares a pair of adjacent atoms with another ring in the system, wherein one or more rings can contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and can be substituted or unsubstituted, and each ring in the fused ring system can contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=0)n, or O, where n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10.

[0058] The term "bridged ring" or "bridged ring group" means a substituted or unsubstituted polycyclic group containing any two non-adjacent atoms, which can contain 0 or more double bonds, and any ring in the bridged ring system can contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=0)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. 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.

[0059] The term "aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, and 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 carbocyclic or heterocyclic ring, wherein the ring connected together with the parent structure is aromatic. Understandably, "arylene" means a divalent group formed by removing one hydrogen atom from aryl.

[0060] The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic or tricyclic ring system having 1 to 10 heteroatoms independently selected from N, O or S, wherein N and S can be optionally oxidized into the various oxidation states, and wherein at least one ring of the ring system is aromatic. Examples of monocyclic heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Examples of bicyclic heteroaryl groups include quinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pteridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzothiadiazinyl, azaindolyl, purine, imidazopyridinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolotriazinyl, oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, indolyl, benzofuranyl, quinoline, isoquinolinyl, indazolyl, indolinyl, isoindolyl, indolizinyl, benzimidazolyl and quinolinyl. Understandably, "heteroarylene" refers to a divalent radical formed by the loss of one hydrogen atom from a heteroaryl group.

[0061] The term "substituted" or "substitution" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, of a group are independently of each other replaced by a corresponding number of substituents. It is within the skill of persons versed in the art to determine, either experimentally or theoretically, what substitutions are possible or impossible. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0062] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and where it does not. For example, "C1-C6 alkyl optionally substituted with halogen or cyano" means that the C1-C6 alkyl group can or can not be substituted with halogen or cyano. 1-6 "Alkyl" means that halogen or cyano can or can not be present, and this description includes instances where the alkyl group is substituted with halogen or cyano and instances where the alkyl group is not substituted with halogen or cyano.

[0063] The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically acceptable carriers, diluents or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption, resulting in the active ingredient exerting a biological effect.

[0064] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" means salts of the compounds of the present application which are optionally selected from inorganic or organic salts. Such salts are safe and effective for use in a mammal, and possess the appropriate biological activity. The salts can be prepared during the final isolation and purification of the compounds, or by separately reacting a suitable base or acid with the compound. Common bases used to form pharmaceutically acceptable salts include inorganic bases such as sodium and potassium hydroxides, and organic bases such as ammonia. Common acids used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0065] The term "pharmaceutically acceptable" means that which is useful in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for its intended use.

[0066] The term "carrier" means a material that does not itself induce the production of antibodies to the biological activity of the biological agent and does not have an adverse effect on the biological activity of the given compound.

[0067] The term "excipient" means an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0068] The term "prodrug" means a compound that can be converted in vivo into a biologically active compound of the present application. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications can be easily removed in vivo to form the parent compound. When the prodrugs of the present application are administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0069] The term "co-crystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are a kind of multi-component crystals, including binary co-crystals formed between two neutral solids, and multi-component co-crystals formed between neutral solids and salts or solvates.

[0070] The term "stereoisomer" means isomers that have the same molecular formula but different structures resulting from the different spatial arrangement of atoms. Stereoisomers include enantiomers and diastereomers.

[0071] The term "tautomers" means isomers that differ in the arrangement of electrons and can be interconverted through a rearrangement (not involving rotation about a bond), such as keto-enol tautomerism and amide-imidol tautomerism.

[0072] The term "preventing and / or treating" includes not only preventing and / or treating a disease, but also generally includes preventing the onset of a disease, slowing or reversing the progression of a disease, preventing or slowing the onset of one or more symptoms associated with a disease, reducing and / or alleviating one or more symptoms associated with a disease, reducing the severity and / or duration of a disease and / or any symptoms associated therewith and / or preventing further increases in the severity of a disease and / or any symptoms associated therewith, preventing, reducing or reversing any physiological damage caused by a disease, and generally any pharmacological action that is beneficial to the patient being treated.

[0073] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be appreciated by those skilled in the art, numbers are often given only to the nearest integer when the parameter is not critical, but for illustrative purposes only and not by way of limitation.

[0074] In the chemical structure of the compounds according to the present application, the bond indicates unspecified configuration, i.e. if chiral isomers are present in the chemical structure, the bond may be or both configurations at the same time.

[0075] In the present application, a single bond connecting a substituent runs through the corresponding ring, the expression that the substituent can be attached to an optional position of the ring, e.g. R is attached to any substitutable position of the phenyl ring.

[0076] The compounds according to the present application can contain one or more asymmetric centers and can thus give rise to diastereomers and optical isomers. All possible diastereomers and their mixtures, as well as all possible geometric isomers and their pharmaceutically acceptable salts are included.

[0077] When tautomers are present for the compounds according to general formula (I), the present application includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof, unless specifically stated otherwise.

[0078] Some examples of the present application provide a fused bicyclic compound or a pharmaceutically acceptable salt thereof, the fused bicyclic compound having the structural characteristics shown in general formula (I) as follows:

[0079] wherein,

[0080] X 1 is independently selected from CR A1 , C(R A1 )2, N, NR A2 , O or S;

[0081] X 2 independently selected from CR A1 , C(R A1 )2, N or NR A2 ;

[0082] X 3 independently selected from C or N;

[0083] X 4 , X 5 , X 6 and X 7 are each independently selected from N or CR A1 ;

[0084] X 8 and X 9 are each independently selected from C or N;

[0085] wherein,

[0086] R A1 is independently selected from H, halogen, cyano, nitro, =0, 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 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 said 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, 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;

[0087] 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 ;

[0088] 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;

[0089] 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;

[0090] 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;

[0091] R A1d and R A2d each independently is selected from H or C 1-3 alkyl;

[0092] said L is selected from or 5- to 6-membered heteroarylene, when L is selected from , it is attached via the carbonyl side to , each of said 5- to 6-membered heteroarylene is optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl;

[0093] wherein,

[0094] R L1 is selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, each of said C 1-6 alkyl or C 3-8 cycloalkyl is optionally substituted with 1-3 substituents independently selected from halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0095] said B ring is selected from C 6-10 arylene or 5- to 10-membered heteroarylene, wherein said 5- to 10-membered heteroarylene contains 1 to 5 heteroatoms selected from N, O, S; wherein a ring carbon atom of said 5- to 10-membered heteroarylene is optionally oxidized to form a carbonyl group; said C 6-10 arylene or 5- to 6-membered heteroarylene is independently substituted with 1-4 substituents independently selected from H, halogen, -OH, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C l-6 haloalkyl, hydroxy-substituted C l-6 alkyl, cyano-substituted C l-6 alkyl, C 3-8cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OR B1a B1a B1a B1a B1a B1a B1a B1b B1c B1b B1c B1b B1c B1b B1c B1d B1a B1d B1a , said 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S;

[0096] B1a B1b B1c each independently selected from H, -NH2, -OH, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl;

[0097] or, R B1b and R B1c together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, or R B1b and R B1c together with the N atom to which they are attached and a further heteroatom selected from O, N or S form a 4- to 6-membered heterocycloalkyl group, wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0098] 1a 1b 2a 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;

[0099] 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;

[0100] 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;

[0101] 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 3-8each of cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 halogen-substituted C 1-6 hydroxy-substituted C 1-6 cyano-substituted C 1-6 C 1-6 halogen-substituted C 1-6 C 3-8 cycloalkyl;

[0102] or, R 3a and R 3b form, together with the N atom to which they are attached, a 3- to 12-membered heterocycloalkyl, or R 3a and R 3b form, together with the N atom to which they are attached and another heteroatom selected from O, N or S, a 3- to 12-membered heterocycloalkyl, wherein said 3- to 12-membered heterocycloalkyl is optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 halogen-substituted C 1-6 hydroxy-substituted C 1-6 cyano-substituted C 1-6 C 1-6 halogen-substituted C 1-6 C 3-8 cycloalkyl;

[0103] ring C is selected from phenyl, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 3-12 cycloalkyl and 3- to 12-membered heterocyclyl are each optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =O, cyano, nitro, -NH2, C 1-6 halogen-substituted C 1-6 hydroxy-substituted C 1-6 cyano-substituted C 1-6 C 1-6 halogen-substituted C 1-6 C 3-8 cycloalkyl or 4- to 7-membered heterocycloalkyl.

[0104] The fused bicyclic compound provided in the application can be used as a METTL3 inhibitor, has good activity, and can be used for preparing a drug for treating and / or preventing a disease related to or mediated by METTL3 activity.

[0105] In some examples, selected from

[0106] m is selected from 0, 1, 2, 3, or 4.

[0107] In some examples, R A1 is independently selected from H, halogen, C 1-6 alkyl, -OR A1a , or -NR A1b R A1c , R A1a , R A1b , R A1c are each independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl, or R A1b and R A1c together with the N atom to which they are attached form a 4- to 9- membered heterocycloalkyl group, optionally R A1b and R A1c together with the N atom to which they are attached form a 4- to 6- membered heterocycloalkyl group.

[0108] In some examples, R A2 is independently selected from H or C 1-6 alkyl; each of said C 1-6 alkyl groups is independently substituted with 1-3 substituents independently selected from H, D, or halogen.

[0109] In some examples, L is selected from or 5-membered heteroarylene, each of said 5-membered heteroarylene is optionally substituted with 1-2 substituents 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, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, or C 3-6 cycloalkyl, said 5-membered heteroarylene contains 1 to 3 heteroatoms selected from N, O, S.

[0110] In some examples, L is selected from oxazolyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, or triazolyl; each of said oxazolyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or triazolyl is optionally substituted with 1-2 substituents independently selected from H, F, Cl, Br, I, -OH, cyano, -NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropyl, or cyclobutyl.

[0111] In some examples, L is selected from

[0112] In some examples, ring B is selected from 5 and 5-membered, 5 and 6-membered, or 6 and 6-membered bicyclic heteroaryl groups, said bicyclic heteroaryl groups containing 1-5 heteroatoms selected from O, S, and N.

[0113] In some examples, ring B is selected from pyrrolopyrrolylene, pyrrolopyrazolylene, pyrroloimidazolylene, pyrazolopyrazolylene, pyrazolimidazolylene, imidazolimidazolylene, benzopyrrolylene, benzopyrazolylene, benzimidazolylene, pyridinopyrrolylene, pyridinopyrazolylene, pyridinimidazolylene, pyrimidinopyrrolylene, pyrimidinopyrazolylene, pyrimidinimidazolylene, pyrazinopyrrolylene, pyrazinopyrazolylene, pyrazinimidazolylene, pyridazinopyrrolylene, pyridazinopyrazolylene, pyridazinimidazolylene, benzopyridylene, benzopyrazylene, benzopyrazylene, benzopyridazylene, pyridinopyridylene, pyridinopyrimidylene, pyridinopyrazinylene, or pyridinopyridazylene.

[0114] In some examples, ring B is selected from benzopyrrolylene, pyridinopyrrolylene, benzopyrazolylene, pyridinopyrazolylene, thiazolopyrrolylene, or benzopyridylene.

[0115] In some examples, ring B is selected from Ring B is attached to R 1a , R 1b substituted carbon;

[0116] wherein,

[0117] n is selected from 0, 1, 2, 3, or 4;

[0118] R B1 is defined the same as R A1 . Without limitation, R B1 each independently is the same or different from R A1 .

[0119] In some examples, R1a R 1b R 2a R 2b each independently is selected from H, deuterium, halogen, cyano, nitro, hydroxyl, -NH2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein said C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl are each optionally substituted with 1-3 substituents 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, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, or C 3-6 cycloalkyl, said heteroaryl containing 1 to 3 heteroatoms selected from N, O, S.

[0120] In some examples, R 1a , R 1b , R 2a , and R 2b each independently is selected from H, F, Cl, Br, I, cyano, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or azetidinyl are each optionally substituted with 1-3 substituents independently selected from H, F, Cl, Br, I, -OH, cyano, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or azetidinyl.

[0121] In some examples, R 1a , R 1b , R 2a , and R 2b each independently is selected from H, F, Cl, Br, I, cyano, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, or azetidinyl.

[0122] In some examples, R 1a , R 1b , R 2a , and R 2beach independently selected from H.

[0123] In some examples, R 3a and R 3b each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, or wherein said C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, are each optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, or C 3-6 cycloalkyl.

[0124] In some examples, R 3a and R 3b each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, azetidinyl, azetidinyl, azetidinyl, phenyl, pyridinyl, or wherein said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, azetidinyl, azetidinyl, azetidinyl, phenyl, pyridinyl, are each optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, or C 3-6 cycloalkyl.

[0125] In some examples, R 3a and R 3b each 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.

[0126] In some of these examples, R 3a and R 3b Choose either H or C 1-6 alkyl.

[0127] In some of these examples, R 3a and R 3b Together 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.

[0128] 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, optionally further substituted with 1-3 substituents selected from the group consisting of H, F, Cl, Br, I, -OH, =0, cyano, -NH2, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, or ethoxy. 1-4 C1-C6alkyl, halogen-substituted C1-C6alkyl, 1-4 C1-C6alkyl, hydroxy-substituted C1-C6alkyl, 1-4 C1-C6alkyl, cyano-substituted C1-C6alkyl, 1-4 C1-C6alkyl, C1-C6alkoxy, 1-4 C1-C6alkyl, halogen-substituted C1-C6alkyl, 1-4 C1-C6alkyl, C1-C6alkoxy, 3-6 cycloalkyl.

[0129] In some examples, R 3a and R 3b together with the N atom to which they are attached form a substituted or unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, pyrrolidinyl spirocyclobutyl, pyrrolidinyl spirocyclopentyl, pyrrolidinyl spirocyclohexyl, piperidinyl spirocyclobutyl, piperidinyl spirocyclopentyl, piperidinyl spirocyclohexyl, when substituted, optionally further substituted with 1-3 substituents selected from the group consisting of H, F, Cl, Br, I, -OH, =0, cyano, -NH2, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, or ethoxy.

[0130] In some examples, R 3a and R 3b together with the N atom to which they are attached form a substituted or unsubstituted when substituted, optionally further substituted with 1-3 substituents selected from the group consisting of H, F, Cl, Br, I, -OH, =0, cyano, -NH2, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, or ethoxy.

[0131] In some examples, ring C is selected from phenyl, C 3-7 monocycloalkyl, C 4-11 bicycloalkyl, C 5-11 spirocycloalkyl, C 5-12 bridged cycloalkyl, 4- to 7-membered monocyclic heterocycloalkyl, 4- to 11-membered bicyclic heterocycloalkyl, 5- to 11-membered spiroheterocycloalkyl, 5- to 12-membered bridged heterocycloalkyl, or phenyl, said heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S, N; said heterocycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halogen, -OH, =0, cyano, nitro, -NH2, C1-C6alkyl, halogen-substituted C1-C6alkyl, 1-4 C1-C6alkyl, halogen-substituted C1-C6alkyl, 1-4 C1-C6alkyl, hydroxy-substituted C1-C6alkyl, 1-4 C1-C6alkyl, cyano-substituted C1-C6alkyl, 1-4 C1-C6alkyl, C1-C6alkoxy, 1-4alkyl, alkoxy, halo-substituted C 1-4 alkyl, alkoxy, halo-substituted C 3-6 cycloalkyl.

[0132] 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, aziridinespirocyclohexylazepanyl, azepinylspirooxepanyl, azepinylspirooxepinyl, azepinylspirooxepinyl, azepinylspirooxepinyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.3.2]decanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.3]undecanyl, adamantyl, when substituted, optionally further substituted with 1-3 selected from H, F, Cl, Br, I, methyl, hydroxyl, =0, methyl, ethyl, propyl, isopropyl, cyclopropyl. 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or C 3-6 cycloalkyl.

[0133] In some examples, ring C is selected from substituted or unsubstituted phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclobutyl, or when substituted, optionally further substituted with 1-3 selected from H, F, Cl, Br, I, methyl, hydroxyl, =0, methyl, ethyl, propyl, isopropyl, cyclopropyl.

[0134] In some examples, the compound is selected from one of the following structures:

[0135] In some examples of the present application, there is provided a pharmaceutical composition comprising a fused bicyclic compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated isotope, solvate, prodrug, metabolite, co-crystal thereof, and a pharmaceutically acceptable carrier.

[0136] In some examples of the present application, there is provided a use of a fused bicyclic compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating and / or preventing a disease associated with or mediated by METTL3 activity.

[0137] In some examples, the disease is selected from a cancer, an autoimmune disease, an inflammatory disease, or autosomal dominant polycystic kidney disease; optionally, the disease is a cancer; further optionally, the cancer is selected from acute myeloid leukemia, 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, cutaneous squamous cell carcinoma, or nasopharyngeal carcinoma; more further optionally, the cancer is acute myeloid leukemia.

[0138] In some examples of the present application, there are provided the fused bicyclic compound or a pharmaceutically acceptable salt thereof as described above or the pharmaceutical composition as described above, and a use of the combination of one or more antitumor drugs in the preparation of a medicament for treating and / or preventing a cancer associated with or mediated by METTL3 activity.

[0139] The antitumor drug is selected from one or more of an alkylating agent, a platinum complex agent, a metabolic antagonist, a plant alkaloid, a hormonal anticancer agent, an antibody drug, a VEGFR or EGFR inhibitor, an mTOR inhibitor, a PI3K kinase inhibitor, a B-Raf inhibitor, an AKT inhibitor, and an immune checkpoint inhibitor. Without limitation, the alkylating agent includes one or more of cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, mechlorethamine hydrochloride, and dibromomannitol; the platinum complex agent includes one or more of cisplatin, carboplatin, 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 leuprolide, goserelin, exemestane, letrozole, anastrozole, and dutasteride; the antibody drug includes one or more of trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, and bevacizumab; the VEGFR or EGFR inhibitor includes one or more of sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, and lapatinib; the mTOR inhibitor includes one or more of everolimus, temsirolimus, and zotarolimus; the PI3K kinase inhibitor includes one or more of BKM-120, XL-147, and BEZ-235; the B-Raf inhibitor includes one or more of vemurafenib and GSK-2118436; the AKT inhibitor includes one or more of perifosine and MK-2206; and the immune checkpoint inhibitor includes one or more of nivolumab and pembrolizumab.

[0140] 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.

[0141] 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.

[0142] The meanings of the abbreviations in the following examples are shown in Table 1:

[0143] Table 1

[0144] The structures of the compounds in the following examples were determined by nuclear magnetic resonance spectroscopy (NMR spectroscopy). 1 Confirmation 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.

[0145] 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.

[0146] The silica gel column chromatography in the following examples uses 200-300 mesh silica gel as the stationary phase.

[0147] 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.

[0148] Unless otherwise specified, the anhydrous solvents used in the following examples were all treated with molecular sieves.

[0149] 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.

[0150] In the following examples, a hydrogen atmosphere refers to a reaction vessel connected to a hydrogen generator at atmospheric pressure.

[0151] In the following examples, the reaction temperature is room temperature, 20-30°C, unless otherwise specified.

[0152] 1 -Methyl- 1 H-pyrrolo [3,2-c]pyridine-3 -carboxylic acid (Intermediate Al)

[0153] Step a: Preparation of Intermediate Al-1

[0154] Methyl 1 H-pyrrolo [3,2-c]pyridine-3 -carboxylate (150.0 mg, 0.85 mmol) was dissolved in DMF (3 mL), Cs2CO3(554.8 mg, 1.70 mmol) was added, and iodomethane (63.6 μL, 1.02 mmol) was added under ice bath. After addition, the temperature was gradually increased to room temperature, and the mixture was stirred at room temperature for 3 hours. TLC detection showed that the reaction was complete. Water (50 mL) was added to quench the reaction, and ethyl acetate (30 mL*3) was used to extract the organic phase. The combined organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to obtain Intermediate Al-1 (81.5 mg, yield 50.3%).

[0155] Step b: Preparation of Intermediate Al

[0156] Intermediate Al-1 (81.5 mg, 0.43 mmol) was dissolved in a mixture of water (1 mL) and MeOH (3 mL), and LiOH-H2O (54.0 mg, 1.29 mmol) was added at room temperature. The mixture was stirred at 50°C for 2 hours. TLC detection showed that the reaction was complete. The reaction was diluted with water, and ethyl acetate (10 mL*3) was used to extract the organic phase. The combined organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Without further purification, a white powdery solid of Intermediate Al (45.1 mg, yield 59.8%) was obtained.

[0157] Preparation of 1 -methyl- 1 H-pyrazolo [4,3 -c]pyridine-3 -carboxylic acid (Intermediate A2) and 2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A3)

[0158] Step a: Preparation of Intermediate A2-1 and A3-1

[0159] Intermediate A2-1: 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, followed by cooling to 0 °C, dropwise addition of iodomethane (288.4 mg, 2.03 mmol) under argon protection, and gradual recovery to room temperature. The solution was stirred at room temperature for 2 h. TLC detection showed that the reaction was complete. The solution was diluted with water and extracted with ethyl acetate (20 mL*3). The organic phase was combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was 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%).

[0160] Intermediate A2-1: 1 H NMR (400 MHz, Chloroform-d) δ 4.57 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.68 (d, J = 6.0 Hz, 2H), 2.65 (t, J = 5.7 Hz, 2H), 1.45 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 309.9 [M+H] + .

[0161] Intermediate A3-1: 1 H NMR (400 MHz, Chloroform-d) δ 4.59 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.11 (s, 3H), 3.67 (d, J = 8.5 Hz, 2H), 2.72 (t, J = 5.9 Hz, 2H), 1.47 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 310.0 [M+H] + .

[0162] Step b: Preparation of intermediates A2-2 and A3-2

[0163] Intermediate A2-1 (160.0 mg, 517.19 µmmol) was dissolved in anhydrous DCM (2 mL), and 4.0 M hydrochloric acid dioxane solution (2 mL) was added dropwise at room temperature and stirred for 1 h. TLC detection showed that the reaction was complete. The solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to obtain yellow solid intermediate A2-2 (114.0 mg, yield 100%). ESI-MS m / z: 209.8 [M+H]+ .

[0164] The preparation method of intermediate A3-2 refers to that of intermediate A2-2.

[0165] ESI-MS m / z: 209.9 [M+H] + .

[0166] Step c: Preparation of intermediates A2-3 and A3-3

[0167] Intermediate A2-2 (114.0 mg, 544.81 pmol) was dissolved in isopropyl benzene (6 mL), 10% palladium on carbon (60.0 mg) was added at room temperature, then the temperature was raised to 160 °C, and refluxed for 24 h. TLC detection showed that the starting material was consumed completely. The solution was concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to give intermediate A2-3 (76.9 mg, yield 69%) as a white solid.

[0168] 1 H NMR (500 MHz, Chloroform-d) d 9.53 (d, J = 1.2 Hz, 1H), 8.53 (d, J = 6.0 Hz, 1H), 7.37 (dd, J = 6.0, 1.2 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 4.17 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 205.8 [M+H] + .

[0169] The preparation method of intermediate A3-3 refers to that of intermediate A2-3.

[0170] 1 H NMR (600 MHz, Chloroform-d) d 9.48 (d, J = 1.4 Hz, 1H), 8.40 (d, J = 6.2 Hz, 1H), 7.60 (dd, J = 6.2, 1.4 Hz, 1H), 4.57 - 4.50 (m, 5H), 1.52 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 205.8 [M+H] + .

[0171] Step d: Preparation of intermediate A2

[0172] Intermediate A2-3 (76.9 mg, 374.73 μmmol) was dissolved in THF (2.5 mL), 1M sodium hydroxide solution (0.5 mL) was added, and stirred at room temperature for 3 hours. TLC detection showed that the starting material was completely consumed. 4.0M hydrochloric acid dioxane solution was added to neutralize to weakly acidic, the solution was concentrated under reduced pressure, and white solid was obtained without purification, which was directly used in the next step reaction. ESI-MS m / z: 177.7 [M+H] + .

[0173] The preparation method of intermediate A3 was referred to the preparation method of intermediate A2. ESI-MS m / z: 177.7 [M+H] + .

[0174] Preparation of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (intermediate A4)

[0175] Step a: preparation of intermediate A4-1

[0176] 3-bromo-1H-pyrazolo[3,4-d]pyrimidine (300.0 mg, 1.51 mmol) was dissolved in DMF (3 mL), Cs2CO3 (982.3 mg, 3.01 mmol) was added, and iodomethane (112.6 μL, 1.81 mmol) was added dropwise under ice bath. After addition, it was gradually warmed to room temperature, and stirred at room temperature for 3 hours. TLC detection showed that the starting material was completely consumed. Water (100 mL) was added to quench, and extracted with ethyl acetate (30 mL*3), and the combined organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain intermediate A4-1 (255.0 mg, yield 97.4%). ESI-MS m / z: 212.6 [M+H] + .

[0177] Step b: preparation of intermediate A4-2

[0178] Intermediate A4-1 (255.0 mg, 1.20 mmol) was dissolved in a mixed solvent of DMF (3 mL) and MeOH (3 mL), 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 successively under argon atmosphere, and the mixture was stirred at 80 °C for 3 h under argon protection. TLC detection showed that the reaction was complete. The reaction solution was filtered, diluted with water, extracted with ethyl acetate (30 mL*3), the combined organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to obtain intermediate A4-2 (55.0 mg, yield 23.8%).

[0179] 1 H NMR (400 MHz, Chloroform-d) δ 9.52 (s, 1H), 9.07 (s, 1H), 4.19 (s, 3H), 4.04 (s, 3H). ESI-MS m / z: 192.9 [M+H] + .

[0180] Step c: Preparation of intermediate A4

[0181] Intermediate A4-2 (55.0 mg, 0.29 mmol) was dissolved in a mixed solvent of water (1 mL) and MeOH (3 mL), and LiOH·H2O (36.0 mg, 0.86 mmol) was added at room temperature, and the mixture was stirred at 50 °C for 2 h. Diluted with water, extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a white powder solid A4 (37.8 mg, yield 74.1%) was obtained without further purification.

[0182] 1 H NMR (400 MHz, Methanol-d4) δ 9.51 (s, 1H), 9.06 (s, 1H), 4.20 (s, 3H). ESI-MS m / z: 178.7 [M+H] + .

[0183] Preparation of 7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (intermediate A5)

[0184] Referring to the preparation method of intermediate A1, 7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester was used instead of 1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid methyl ester to obtain white solid intermediate A5. ESI-MS m / z: 177.8 [M+H]+ .

[0185] 5-(tert-Butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A6)

[0186] 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] + .

[0187] 1-Methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (intermediate A7)

[0188] 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] + .

[0189] Imidazo[1,5-a]pyrazine-1-carboxylic acid (intermediate A8)

[0190] 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] + .

[0191] 3-Methylimidazo[1,5-a]pyrazine-1-carboxylic acid (intermediate A9)

[0192] Step a: Synthesis of intermediate A9-1

[0193] 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%). 1H NMR (400 MHz, Chloroform-d) δ 8.95 - 8.87 (m, 1H), 7.72 (d, J = 1.0 Hz, 1H), 7.57 (dt, J = 5.2, 1.3 Hz, 1H), 7.52 (d, J = 5.1 Hz, 1H), 2.68 (s, 3H). ESI-MS m / z: 133.8 [M+H] + .

[0194] Step b: synthesis of intermediate A9-2

[0195] To a single-neck flask was added compound A9-1 (2.74 g, 18.15 mmol) dissolved in phosphorus oxychloride (10 mL), DMF (1 mL) was added, heated to 55 °C and stirred for 3 hours. TLC showed no starting material remained. Ice bath, ammonia gas methanol (500 mL) was added to quench the reaction and concentrated under reduced pressure, the crude product was separated and purified by column chromatography to obtain a white solid (889 mg, yield 36.8%).

[0196] 1 H NMR (400 MHz, Chloroform-d) δ 8.95 - 8.87 (m, 1H), 7.72 (d, J = 1.0 Hz, 1H), 7.57 (dt, J = 5.2, 1.3 Hz, 1H), 7.52 (d, J = 5.1 Hz, 1H), 2.68 (s, 3H). ESI-MS m / z: 133.8 [M+H] + .

[0197] Step c: synthesis of intermediate A9-3

[0198] To a single-neck flask was added compound A9-2 (889.0 mg, 6.68 mmol) dissolved in DMF (30 mL), N-iodosuccinimide (1.65 g, 7.34 mmol) was added to the above solution, and the reaction was carried out at room temperature for 2 hours. TLC showed no starting material remained. To the reaction was added saturated sodium thiosulfate solution (50 mL) to quench the reaction, extracted with EA (2 x 50 mL), the organic phase was washed with water (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain a yellow solid (1.0 g, yield 57.8%).

[0199] 1H NMR (400 MHz, 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] + .

[0200] Step d: Synthesis of intermediate A9-4

[0201] To a sealed tube was added compound A9-3 (1.0 g, 3.86 mmol), molybdenum hexacarbonyl (10.19 g, 38.60 mmol), dissolved in DMF:MeOH (1:1, v / v, 100 mL), triethylamine (1.2 g, 11.58 mmol) was added, purged with argon three times, tetrakis(triphenylphosphine)palladium (1.34 g, 1.16 mmol) was added, heated to 80 °C for 12 hours. TLC showed no starting material remained, saturated ammonium chloride solution (200 mL) was added to the reaction, extracted with EA (2 x 200 mL), the organic phase was washed with water (200 mL), saturated brine (200 mL), the organic phase was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, the crude product was separated and purified by column chromatography to obtain a white solid (250.0 mg, yield 33.9%).

[0202] 1 H NMR (400 MHz, Chloroform-d) δ 9.57 (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] + .

[0203] Step e: Synthesis of intermediate A9

[0204] Referring to the preparation method of intermediate Al, intermediate A9 was obtained as a white solid from intermediate A9-4.

[0205] 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)

[0206] Referring to the preparation methods of intermediates A2 and A3, intermediate A10 and A11 were obtained as white solids by replacing iodomethane with iodoethane.

[0207] A10: ESI-MS m / z: 191.9 [M+H]+ A11: ESI-MS m / z: 191.9 [M+H] + .

[0208] Preparation of 1-isopropyl-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A12) & 2-isopropyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A13)

[0209] Following the procedure for the preparation of Intermediate A2 and A3, using isopropyl iodide instead of methyl iodide, Intermediate A12 and A13 were obtained as white solids.

[0210] A12: ESI-MS m / z: 205.8 [M+H] + A13: ESI-MS m / z: 205.8 [M+H] + .

[0211] Preparation of 1-(2,2,2-trifluoroethyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A14)

[0212] Following the procedure for the preparation of Intermediate A2, using 2,2,2- trifluoroethyl trifluoromethanesulfonate instead of methyl iodide, Intermediate A14 was obtained as a white solid. ESI-MS m / z: 245.8 [M+H] + .

[0213] Preparation of 1-(2,2-difluoroethyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A15)

[0214] Following the procedure for the preparation of Intermediate A2, using 1,1- difluoro-2-iodoethane instead of methyl iodide, Intermediate A15 was obtained as a white solid.

[0215] Preparation of 1-(methyl-d3)-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A16)

[0216] Following the procedure for the preparation of Intermediate A2, using deuterated methyl iodide instead of methyl iodide, Intermediate A16 was obtained as a white solid. ESI-MS m / z: 180.8 [M+H] + .

[0217] 1,7-Dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A17)

[0218] Step a: Synthesis of Intermediate A17-1

[0219] 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 was placed at -78 °C, and LDA (2.0 M in THF, 2.81 mmol) was added dropwise. The stirring was continued for 1 h, and then diethyl oxalate (342.6 mg, 2.34 mmol) was added dropwise to the reaction, and the temperature was slowly increased to room temperature. The stirring was continued for 2 h. TLC monitoring showed that the starting material was consumed completely. 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 give a yellow oily liquid racemic mixture (373.0 mg, 51% yield). ESI-MS m / z: 311.9 [M-H] - .

[0220] Step b: synthesis of intermediate A17-2

[0221] 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 stirring was continued at room temperature for 2 h. TLC monitoring showed that the starting material was consumed completely. The reaction was neutralized with saturated sodium bicarbonate solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give a light yellow oily liquid (373.0 mg, 100% yield). ESI-MS m / z: 309.9 [M+H] + .

[0222] Step c-f: synthesis of intermediate A17

[0223] Following the preparation method of intermediate A2, intermediate A17-2 was replaced with 5-tert-butyl-3-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid to give intermediate A17 as a white solid. ESI-MS m / z: 191.8 [M+H] + .

[0224] 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A18)

[0225] Following the preparation method of intermediate A17, 1-tert-butoxycarbonyl-2-methyl-piperidin-4-one gave intermediate A18 as a white solid. ESI-MS m / z: 191.9 [M+H] + .

[0226] 7-bromo-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate A19)

[0227] Step a: Synthesis of intermediate A19-1

[0228] Intermediate A2-3 (5.0 g, 24.36 mmol) was dissolved in DMF (5 mL), N- bromosuccinimide (8.7 g, 48.73 mmol) was added, warmed to 80 °C and stirred overnight. TLC detection showed the reaction was complete. The reaction was diluted with water, extracted with EA, washed with saturated sodium thiosulfate solution and saturated brine solution respectively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography gave intermediate A19-1 (4.8 g, yield 69%) as a yellow solid. ESI-MS m / z: 283.9 [M+H] + .

[0229] Step b: Synthesis of intermediate A19

[0230] Intermediate A19 was prepared from intermediate A19-1 according to the synthetic method of intermediate A2. ESI-MS m / z: 256.0 [M+H] + .

[0231] 7-((2,4-Dimethoxybenzyl)(methyl)amino)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3- carboxylic acid ethyl ester (intermediate A20)

[0232] Step a: Synthesis of intermediate A20-1

[0233] Intermediate A19-1 (500.0 mg, 1.76 mmol), 2,4-dimethoxy-N-methylbenzylamine (478.4 mg, 2.64 mmol), tris(dibenzylideneacetone)dipalladium (161.2 mg, 0.18 mmol), 2- dicyclohexylphosphino-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), replaced with argon for three times, warmed to 100 °C and stirred overnight. TLC detection showed the reaction was complete. Concentrated under reduced pressure, the crude product was purified by column chromatography to give intermediate A20-1 (237.0 mg, yield 35%) as a yellow oil. ESI-MS m / z: 384.9 [M+H] + .

[0234] Step b: Synthesis of intermediate A20

[0235] Intermediate A20 was prepared from intermediate A20-1 according to the synthetic method of intermediate A2. ESI-MS m / z: 356.8 [M+H]+ .

[0236] 1 -Methyl-7-(methyl-d3)- 1 H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate A21)

[0237] Step a: synthesis of intermediate A21-1

[0238] N-tert-Butoxycarbonyl-4-piperidinone (10.0 g, 50.19 mmol) was dissolved in anhydrous THF (100 mL) and cooled to -78 °C, then 2.0 M lithium diisopropylamide solution (37.5 mL, 75.28 mmol) was added dropwise slowly, after stirring for 30 min, deuterated iodomethane (8.0 g, 55.21 mmol) was added dropwise, and stirring was continued for 2 h. TLC detection showed that the reaction was complete. Quenching was performed by adding saturated ammonium chloride solution, and extraction was performed with EA. The organic phase was 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%).

[0239] Step b-g: synthesis of intermediate A21

[0240] Referring to the synthesis method of intermediate A17, intermediate A21 was obtained by replacing N-Boc-3-methyl-piperidin-4-one with intermediate A21-1. ESI-MS m / z: 194.9 [M+H] + .

[0241] Preparation of (2-(diethoxymethyl)- 1 H-indol-6-yl)methanamine (Intermediate B1)

[0242] Step a: preparation of intermediate B1-1

[0243] 3-Amino-4-iodobenzonitrile (1.0 g, 4.46 mmol) was dissolved in THF (10 mL), and 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. The reaction vessel was replaced with argon three times, and stirring was continued at room temperature for 16 h. TLC detection showed that the reaction was complete. 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 a crude product, which was purified by column chromatography on silica gel (PE / EA = 10 / 1) to obtain intermediate B1-1 (1.0 g, yield 91.8%).

[0244] 1H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.59 (s, 1H), 5.78 (s, 1H), 3.65 (q, J = 7.9 Hz, 4H), 1.27 (t, J = 7.2 Hz, 6H).

[0245] Step b: Preparation of Intermediate B1-2

[0246] Intermediate B1-1 (1.0 g, 4.09 mmol) was dissolved in NMP (10 mL), potassium tert-butoxide (919.2 mg, 8.19 mmol) was added under ice-bath, after addition, it was warmed to room temperature and stirred for 18 hours. TLC detection showed that the reaction was complete. Quenching with saturated ammonium chloride solution (100 mL), ethyl acetate extraction (30 mL*3), the combined organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product, which was separated and purified by silica gel column chromatography (PE / EA = 20 / 1) to give intermediate B1-2 (412.4 mg, yield 41.2%).

[0247] 1 H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.59 (s, 1H), 5.78 (s, 1H), 3.65 (q, J = 7.9 Hz, 4H), 1.27 (t, J = 7.2 Hz, 6H).

[0248] Step c: Preparation of Intermediate B1

[0249] Intermediate B1-2 (300.0 mg, 1.22 mmol) was dissolved in ethanol (5 mL), 7.0 M ammonium methanol solution (3.0 mL) and Raney nickel (432.7 mg, 6.0 mmol) were added in turn at room temperature, after addition, it was replaced with argon for three times, filled with hydrogen, and stirred at 50°C for 5 hours under hydrogen atmosphere. TLC detection showed that the reaction was complete. The reaction solution was filtered, the filter cake was washed with methanol (15 mL*2), the filtrate was collected and concentrated, and the crude product was separated and purified by silica gel column chromatography (DCM / MeOH·NH3= 50 / 1) to give intermediate B1 (200.0 mg, yield 67.8%).

[0250] 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 6.94 (dd, J = 8.1, 1.5 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 5.67 (s, 1H), 3.76 (s, 2H), 3.62 - 3.49 (m, 4H), 2.09 - 1.68 (br s, 2H), 1.17 (t, J = 7.0 Hz, 6H).

[0251] (2-(Diethylcarbamoyl)-l-methyl-lH-indol-6-yl)methanamine (Intermediate B2)

[0252] Step a: Synthesis of Intermediate B2-1

[0253] Intermediate B2-1 (600.0 mg, 2.46 mmol) was dissolved in dry DMF, sodium hydride (245.6 mg, 6.14 mmol) was added under ice bath, after 10 minutes stirring at room temperature, iodomethane (697.2 mg, 4.91 mmol) was added dropwise under ice bath, stirred at room temperature for 1 hour. TLC monitored the complete consumption of starting material. Quenched with water, EA extraction, saturated brine washing, dried over anhydrous sodium sulfate, separated and purified by column chromatography, to prepare a light yellow oily liquid (609.3 mg, yield 96%).

[0254] 1 H NMR (400 MHz, Chloroform-d) δ 7.69 - 7.58 (m, 2H), 7.31 (dd, J = 8.2, 1.4 Hz, 1H), 6.65 (d, J = 1.0 Hz, 1H), 5.67 (s, 1H), 3.84 (s, 3H), 3.72 - 3.54 (m, 4H), 1.24 (t, J = 7.1 Hz, 6H). ESI-MS m / z: 258.9 [M+H] + .

[0255] Step b: Synthesis of Intermediate B2

[0256] Referring to the preparation method of Intermediate Bl, Intermediate B2-1 was used instead of Bl-2 to obtain yellow solid of Intermediate B2.

[0257] 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.03 (dd, J = 8.1, 1.4 Hz, 1H), 6.56 (d, J = 2.9 Hz, 1H), 5.83 - 5.53 (m, 1H), 3.99 (s, 2H), 3.81 (d, J = 1.8 Hz, 3H), 3.68 - 3.54 (m, 4H), 1.23 (t, J = 7.1 Hz, 6H). ESI-MS m / z: 262.8 [M+H] + .

[0258] (2-(Diethylaminomethyl)-lH-indol-6-yl)methanamine (Intermediate B2)

[0259] Referring to the preparation method of Intermediate Bl, 5-amino-4-bromo-2- fluorobenzonitrile was used to replace 3-amino-4-iodobenzonitrile to obtain yellow oily liquid Intermediate B3. ESI-MS m / z: 266.8 [M+H] + .

[0260] (7-(Diethylaminomethyl)-l-methoxyisoquinolin-3-yl)methanamine (Intermediate B4)

[0261] Step a: synthesis of Intermediate B4-1

[0262] 6-bromo-l,3-dichloroisoquinoline (2.0 g, 7.22 mmol) was dissolved in methanol (25 mL), sodium methoxide (780.3 mg, 14.44 mmol) was added, and stirred at 80 °C for 16 hours. TLC detection showed that the raw material was completely reacted. Diluted with water, filtered, the filter cake was washed with ethyl acetate to obtain light yellow solid (1.7 g, yield 86%). ESI-MS m / z: 272.1 [M+H] + .

[0263] Step b: synthesis of Intermediate B4-2

[0264] Intermediate B4-1 (1.7 g, 6.24 mmol) was dissolved in anhydrous THF (20 mL) and cooled to -78 °C. 2.5 M n-BuLi (3.8 mL, 9.36 mmol) was added slowly dropwise. After stirring for 30 min, N,N-dimethylformamide (912.0 mg, 12.48 mmol) was added and stirring was continued for 3 h. TLC indicated that the starting material was consumed completely. The reaction was quenched by the addition of saturated ammonium chloride solution. EA extraction, saturated brine washing, anhydrous sodium sulfate drying, and concentration under reduced pressure gave a crude product, which was purified by column chromatography to give a yellow oily liquid (750.0 mg, yield 54%). ESI-MS m / z: 221.9 [M+H] + .

[0265] Step c: synthesis of intermediate B4-3

[0266] Intermediate B4-2 (750.0 mg, 3.38 mmol) was dissolved in ethanol (10 mL), and then triethyl orthoformate (501.5 mg, 3.38 mmol) and TsOH (582.7 mg, 3.38 mmol) were added. The reaction was stirred at 80 °C overnight. TLC indicated that the starting material was consumed completely. The reaction was concentrated under reduced pressure, and then purified by column chromatography to give a yellow oily liquid (840 mg, yield 84%). ESI-MS m / z: 295.9 [M+H] + .

[0267] Step d: synthesis of intermediate B4-4

[0268] Intermediate B4-3 (840 mg, 2.84 mmol) and zinc cyanide (500.0 mg, 4.26 mmol) were dissolved in anhydrous DMF (15 mL), and then the reaction was purged with argon for 5 min. 1,1-Bis(diphenylphosphino)ferrocene palladium dichloride (207.8 mg, 0.28 mmol) was added, and the reaction was stirred at 100 °C overnight under argon. TLC indicated that the starting material was consumed completely. The reaction 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, yield 52%). ESI-MS m / z: 287.1 [M+H] + .

[0269] Step e: synthesis of intermediate B4

[0270] Intermediate B4 was prepared according to the procedure for the preparation of intermediate B1, using intermediate B4-4 instead of intermediate B1-2. ESI-MS m / z: 291.1 [M+H] + .

[0271] (7-(diethoxymethyl)-1-methoxyisoquinolin-3-yl)methanamine (intermediate B5)

[0272] Step a: Synthesis of intermediate B5-1

[0273] Following the procedure for the preparation of intermediate B4-2, replacing intermediate B4-1 with 6-bromo-l,3-dichloroisoquinoline, intermediate B5-1 was prepared as a yellow oil liquid. ESI-MS m / z: 225.8 [M+H] + .

[0274] Step b: Synthesis of intermediate B5-2

[0275] Following the procedure for the preparation of intermediate B4-3, replacing intermediate B4-2 with intermediate B5-1, intermediate B5-2 was prepared as a yellow oil liquid. ESI-MS m / z: 299.8 [M+H] + .

[0276] Step c: Synthesis of intermediate B5-3

[0277] 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 palladium (Pd) dichloride bis(triphenylphosphine) (130.4 mg, 0.18 mmol) were dissolved in a mixed solution of 1,4-dioxane / water (10 mL, v / v = 4 / 1) and stirred at 100 °C for 4 h under argon atmosphere. TLC detection showed that the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give intermediate B5-3 (315 mg, yield 63%) as a yellow oil liquid. ESI-MS m / z: 280.2 [M+H] + .

[0278] Step d: Synthesis of intermediate B5-4

[0279] Following the procedure for the preparation of intermediate B4-4, replacing intermediate B4-3 with intermediate B5-3, intermediate B5-4 was prepared as a yellow solid. ESI-MS m / z: 270.8 [M+H] + .

[0280] Step e: Synthesis of intermediate B5

[0281] Following the procedure for the preparation of intermediate B4, replacing intermediate B4-4 with intermediate B5-4, intermediate B5 was prepared as a yellow oil liquid. ESI-MS m / z: 274.9 [M+H] + .

[0282] Example 1: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)pyrazolo[l,5-a]pyrazine-3-carboxamide (Compound 1)

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

[0284] Pyrrolo[l,2-a]pyrazine-8-carboxylic acid (44.0 mg, 0.18 mmol) was dissolved in DMF (2 mL), DIPEA (92.7 μL, 0.53 mmol) and HATU (80.9 mg, 0.21 mmol) were added successively, and stirred at room temperature for 30 min. Then the DMF solution of intermediate B1 was added dropwise into the reaction solution, and stirred at room temperature for 6 h. TLC detection showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution (50 mL) was added to quench, and extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-1 (47.5 mg, yield 68.1%), which was used directly in the next step.

[0285] Step b: Synthesis of intermediate 1-2

[0286] Intermediate 1-1 (47.5 mg, 0.12 mmol) was dissolved in a mixture solvent of THF (5 mL) and water (0.5 mL), glacial acetic acid (0.5 mL) was added dropwise, and stirred at room temperature for 2 h. TLC detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, water (20 mL) was added, a large amount of solid was precipitated, filtered, and the filter cake was washed with water (5 mL*3) and diethyl ether (5 mL*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] + .

[0287] Step c: Synthesis of Compound 1

[0288] Intermediate 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 h. The reaction was cooled to room temperature, then STAB (75.5 mg, 0.36 mmol) was added, and the mixture was stirred at 65 °C for 2 h. TLC detection showed that the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by pre-TLC (DCM / MeOH·NH3=8 / 1) to give compound 1 (24.1 mg, yield 52.3%).

[0289] 1 H NMR (400 MHz, Chloroform-d) δ 9.73 (d, J = 1.4 Hz, 1H), 8.81 (s, 1H), 8.33 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (s, 1H), 7.98 (d, J = 4.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.03 (dd, J = 8.1, 1.5 Hz, 1H), 6.66 (t, J = 5.5 Hz, 1H), 6.40 - 6.18 (m, 1H), 4.69 (d, J = 5.5 Hz, 2H), 3.90 (s, 2H), 2.64 (d, J = 7.3 Hz, 2H), 2.46 (p, J = 7.6 Hz, 1H), 2.03 (qdd, J = 7.5, 3.9, 1.6 Hz, 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] + .

[0290] Example 2: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrrolo[3,2-c]pyridine-3-carboxamide (Compound 2)

[0291] Step a: Synthesis of Intermediate 2-1

[0292] Intermediate A1 (45.1 mg, 0.26 mmol) was dissolved in DMF (2 mL), DIPEA (111.6 μL, 0.64 mmol) and HATU (97.5 mg, 0.26 mmol) were added successively, and stirred at room temperature for 30 min. Then a DMF solution of B1 was added dropwise to the reaction solution, and stirred at room temperature for 6 h. TLC detection showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution (50 mL) was added to quench, and extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude 2-1 (50.0 mg, yield 67.7%), which was directly used in the next step.

[0293] Step b: synthesis of intermediate 2-2

[0294] Intermediate 2-1 (50.0 mg, 0.12 mmol) was dissolved in a mixture of THF (5 mL) and water (0.5 mL), and glacial acetic acid (0.5 mL) was added dropwise, and stirred at room temperature for 2 h. TLC detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was separated and 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] + .

[0295] Step c: synthesis of compound 2

[0296] 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 h. The reaction was cooled to room temperature, then STAB (73.9 mg, 0.35 mmol) was added, and the temperature was raised to 65 °C and stirred for 2 h. TLC detection showed that the reaction was complete. Saturated sodium bicarbonate solution (10 mL) was added to quench, and extracted with ethyl acetate (10 mL*3), the combined organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was separated and purified by pre-TLC (DCM / MeOH·NH3=10 / 1) to give compound 2 (17.6 mg, yield 37.7%).

[0297] 1H NMR (400 MHz, Chloroform-d) δ 9.30 (d, J = 1.1 Hz, 1H), 9.28 - 9.22 (m, 1H), 8.31 (d, J = 5.8 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.14 (dd, J = 5.9, 1.1 Hz, 1H), 7.03 (dd, J = 8.1, 1.5 Hz, 1H), 6.66 (t, J = 5.5 Hz, 1H), 6.26 (d, J = 1.7 Hz, 1H), 4.66 (d, J = 5.5 Hz, 2H), 3.87 (s, 2H), 3.65 (s, 3H), 2.62 (d, J = 7.3 Hz, 2H), 2.44 (p, J = 7.7 Hz, 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] + .

[0298] Example 3: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 3)

[0299] Step a: Synthesis of intermediate 3-1

[0300] Intermediate A2 (32.7 mg, 0.18 mmol) was dissolved in DMF (2 mL), DIPEA (59.7 μL, 0.46 mmol) and HATU (70.2 mg, 0.18 mmol) were added successively, stirred at room temperature for 30 min. Then the DMF solution of B1 was added slowly dropwise into the reaction, reacted at room temperature for 6 h. TLC detection showed that the raw material was completely reacted. Quenching was carried out by adding saturated aqueous sodium bicarbonate solution (50 mL), and ethyl acetate extraction (20 mL*3), the combined organic phase was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 3-1 (21.7 mg, yield 40.4%), which was directly used in the next step.

[0301] Step b: Synthesis of intermediate 3-2

[0302] Intermediate 3-1 (21.8 mg, 0.065 mmol) was dissolved in a mixture solvent of THF (5 mL) and water (0.5 mL), glacial acetic acid (0.5 mL) was added dropwise, and stirred at room temperature for 2 hours. TLC detection of the raw material reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by pre-TLC separation (DCM / MeOH-NH3=10 / 1) to obtain intermediate 3-2 (14.2 mg, yield 82.4%).

[0303] 1 H NMR (400 MHz, Methanol-d4) δ 9.77 (s, 1H), 9.47 (d, J = 1.3 Hz, 1H), 8.40 (d, J = 6.2 Hz, 1H), 7.72-7.65 (m, 2H), 7.50 (s, 1H), 7.33-7.26 (m, 1H), 7.19 (dd, J = 8.3, 1.5 Hz, 1H), 4.74 (s, 2H), 4.16 (s, 3H). ESI-MS m / z: 333.9 [M+H] + .

[0304] Step c: synthesis of compound 3

[0305] 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, then STAB (26.8 mg, 0.126 mmol) was added, and after addition, the temperature was increased to 65°C and stirred for 2 hours. TLC detection of the raw material reaction was complete. Quenching was performed by adding saturated sodium bicarbonate solution (10 mL), and ethyl acetate extraction (10 mL*3) was performed, and the combined organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by pre-TLC separation (DCM / MeOH-NH3=10 / 1) to obtain compound 3 (7.0 mg, yield 40.8%).

[0306] 1H NMR (400 MHz, Chloroform-d) δ 9.72 (d, J = 1.3 Hz, 1H), 8.74 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J = 1.3 Hz, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.11 (dd, J = 8.1, 1.5 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H), 4.05 (s, 3H), 3.94 (s, 2H), 2.65 (d, J = 7.2 Hz, 2H), 2.47 (p, J = 7.6 Hz, 1H), 2.22 (t, J = 7.6 Hz, 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] + .

[0307] Example 4: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[3,4-d]pyrimidine-3-carboxamide (Compound 4)

[0308] Step a: Synthesis of intermediate 4-1

[0309] Intermediate A4 (37.8 mg, 0.21 mmol) was dissolved in DMF (2 mL), DIPEA (93.8 μL, 0.53 mmol) and HATU (63.7 mg, 0.18 mmol) were added successively, stirred at room temperature for 30 min. Then the DMF solution of B1 was added dropwise into the reaction solution, reacted at room temperature for 6 h. TLC detection showed that the raw material was completely reacted. Quenching was performed by adding saturated aqueous sodium bicarbonate solution (50 mL), and ethyl acetate extraction (20 mL*3), the combined organic phase was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 4-1 (23.7 mg, yield 38.1%), which was directly used in the next step.

[0310] Step b: Synthesis of intermediate 4-2

[0311] Intermediate 4-1 (23.7 mg, 0.071 mmol) was dissolved in a mixture solvent of THF (5 mL) and water (0.5 mL), glacial acetic acid (0.5 mL) was added dropwise, and stirred at room temperature for 2 hours. TLC detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by pre-TLC separation (DCM / MeOH-NH3=10 / 1) to obtain intermediate 4-2 (14.7 mg, yield 82.4%).

[0312] 1 H NMR (400 MHz, Methanol-d4) δ 10.09 (s, 1H), 9.77 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.37-7.33 (m, 1H), 7.29 (s, 1H), 7.13 (dd, J = 8.4, 1.5 Hz, 1H), 4.64 (s, 2H), 3.63 (s, 3H). ESI-MS m / z: 334.9 [M+H] + .

[0313] Step c: synthesis of compound 4

[0314] 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, then STAB (27.6 mg, 0.136 mmol) was added, and after addition, the temperature was increased to 65°C and stirred for 2 hours. TLC detection showed that the reaction was complete. Saturated sodium bicarbonate solution (10 mL) was added to quench, and ethyl acetate was extracted (10 mL*3), the combined organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by pre-TLC separation (DCM / MeOH-NH3=8 / 1) to obtain compound 4 (8.0 mg, yield 45.1%).

[0315] 1 ​​H NMR (400 MHz, Chloroform-d) δ 9.74 (s, 1H), 9.08 (s, 1H), 8.78 - 8.71 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.31 (s, 1H), 7.10 (dd, J = 8.1, 1.5 Hz, 1H), 6.32 (dd, J = 2.0, 0.9 Hz, 1H), 4.76 (d, J = 5.8 Hz, 2H), 4.11 (s, 3H), 3.98 - 3.90 (m, 2H), 2.65 (d, J = 7.3 Hz, 2H), 2.48 (dq, J = 15.2, 7.7 Hz, 1H), 2.04 (dddd, J = 11.3, 9.2, 7.8, 4.5 Hz, 2H), 1.95 - 1.80 (m, 2H), 1.69 - 1.63 (m, 2H). ESI-MS m / z: 402.0 [M-H] - .

[0316] Example 5: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (Compound 5)

[0317] Compound 5 was prepared as a white solid from intermediate A5 using the method described in Compound 1.

[0318] 1 H NMR (500 MHz, Methanol-d4) δ 9.54 (s, 1H), 9.09 (s, 1H), 8.32 (s, 1H), 7.54 (dd, J = 8.2, 0.7 Hz, 1H), 7.45 (dd, J = 1.6, 0.9 Hz, 1H), 7.12 (dd, J = 8.2, 1.5 Hz, 1H), 6.62 (d, J = 0.8 Hz, 1H), 4.69 (s, 2H), 4.34 (s, 2H), 4.00 (s, 3H), 3.09 (d, J = 7.5 Hz, 2H), 2.68 (hept, J = 7.8 Hz, 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] + .

[0319] Example 6: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 6)

[0320] Using the procedure described in compound 1 from intermediate A6, compound 6 was prepared as a yellow solid.

[0321] 1 H NMR (500 MHz, Methanol-d4) δ 7.42 (dd, J = 8.1, 0.7 Hz, 1H), 7.30 (dt, J = 1.6, 0.8 Hz, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.31 (d, J = 0.9 Hz, 1H), 4.58 (s, 2H), 3.99 (d, J = 1.3 Hz, 2H), 3.90 - 3.84 (m, 2H), 3.74 (s, 3H), 3.04 (t, J = 5.9 Hz, 2H), 2.68 - 2.62 (m, 4H), 2.55 - 2.45 (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] + .

[0322] Example 7: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-indazole-3-carboxamide (Compound 7)

[0323] Using the procedure described in compound 1 from l-methyl-3-indazolecarboxylic acid, compound 7 was prepared as a white solid.

[0324] 1 H NMR (500 MHz, Methanol-d4) δ 8.23 (dt, J = 8.2, 1.1 Hz, 1H), 7.56 (dd, J = 8.5, 5.1 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.39 - 7.35 (m, 1H), 7.26 (dddd, J = 8.0, 6.9, 2.4, 0.9 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.31 (t, J = 1.0 Hz, 1H), 4.69 (s, 2H), 4.09 (d, J = 4.7 Hz, 3H), 3.85 (d, J = 1.8 Hz, 2H), 2.61 (dd, J = 7.4, 1.9 Hz, 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] + .

[0325] Example 8: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[3,4-b]pyridine-3-carboxamide (Compound 8)

[0326] Compound 8 was prepared as a white solid from l-methyl-lH-pyrazolo[3,4- b]pyridine-3-carboxylic acid using the method described in Compound 1.

[0327] 1 H NMR (500 MHz, Methanol-d4) δ 8.62 - 8.53 (m, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.30 (dd, J = 8.1, 4.6 Hz, 1H), 7.04 (dd, J = 8.2, 1.5 Hz, 1H), 6.30 (d, J = 1.1 Hz, 1H), 4.69 (s, 2H), 4.14 (d, J = 4.6 Hz, 3H), 3.85 (d, J = 2.4 Hz, 2H), 2.61 (dd, J = 7.4, 2.5 Hz, 2H), 2.48 (hept, J = 7.7 Hz, 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] + .

[0328] Example 9: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 9)

[0329] Compound 9 was prepared as a white solid from intermediate A7 using the method described in Compound 1.

[0330] 1H NMR (500 MHz, Methanol-d4) δ 9.10 (d, J = 1.3 Hz, 1H), 8.32 (d, J = 5.7 Hz, 1H), 8.17 (dd, J = 5.7, 1.3 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 1.0 Hz, 1H), 4.70 (s, 2H), 4.24 (s, 3H), 3.85 (s, 2H), 2.61 (d, J = 7.3 Hz, 2H), 2.49 (hept, J = 7.7 Hz, 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] + .

[0331] Example 12: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)imidazo[l,5-a]pyrazine-l-carboxamide (Compound 12)

[0332] Compound 12 was prepared as a white solid from intermediate A8 using the method described in Compound 1.

[0333] 1 H NMR (500 MHz, Methanol-d4) δ 9.10 (d, J = 1.3 Hz, 1H), 8.32 (d, J = 5.7 Hz, 1H), 8.17 (dd, J = 5.7, 1.3 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 1.0 Hz, 1H), 4.70 (s, 2H), 4.24 (s, 3H), 3.85 (s, 2H), 2.61 (d, J = 7.3 Hz, 2H), 2.49 (hept, J = 7.7 Hz, 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] + .

[0334] Example 13: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-3-methylimidazo[l,5-a]pyrazine-l-carboxamide (Compound 13)

[0335] Using the method described in compound 1, compound 13 was prepared from intermediate A9 as a white solid.

[0336] 1 H NMR (600 MHz, DMSO-d6) δ 10.83 (d, J = 2.3 Hz, 1H), 9.43 (d, J = 1.6 Hz, 1H), 8.76 (t, J = 6.4 Hz, 1H), 8.26 (dd, J = 5.0, 1.6 Hz, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 6.96 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 - 6.16 (m, 1H), 4.54 (d, J = 6.3 Hz, 2H), 3.77 (s, 2H), 2.66 (s, 3H), 2.52 - 2.51 (m, 2H), 2.39 (p, J = 7.5 Hz, 1H), 1.96 (tdd, J = 7.9, 4.9, 3.1 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.64 - 1.56 (m, 2H). ESI-MS m / z: 403.2 [M+H] + .

[0337] Example 16: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-ethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 16)

[0338] Using the method described in compound 1, compound 16 was prepared from intermediate A10 as a white solid.

[0339] 1H NMR (500 MHz, Methanol-d4) δ 9.71 (s, 1H), 8.58 (d, J = 6.9 Hz, 1H), 8.27 (d, J = 6.9 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.47 (dt, J = 1.6, 0.8 Hz, 1H), 7.15 (dd, J = 8.2, 1.5 Hz, 1H), 6.61 (d, J = 0.9 Hz, 1H), 4.74 (s, 2H), 4.69 (q, J = 7.3 Hz, 2H), 4.34 (s, 2H), 3.08 (d, J = 7.5 Hz, 2H), 2.68 (hept, J = 7.8 Hz, 1H), 2.21 - 2.12 (m, 2H), 2.04 - 1.93 (m, 1H), 1.91 - 1.78 (m, 3H), 1.61 (t, J = 7.3 Hz, 3H). ESI-MS m / z: 417.0 [M+H] + .

[0340] Example 17: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-isopropyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 17)

[0341] Compound 17 was prepared as a white solid from intermediate Al 2 using the method described in Compound 1.

[0342] 1 H NMR (500 MHz, Methanol-d4) δ 9.72 (s, 1H), 8.58 (d, J = 6.9 Hz, 1H), 8.31 (d, J = 6.9 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.50 - 7.46 (m, 1H), 7.16 (dd, J = 8.2, 1.5 Hz, 1H), 6.62 (d, J = 0.9 Hz, 1H), 5.24 (hept, J = 6.6 Hz, 1H), 4.75 (s, 2H), 4.34 (s, 2H), 3.08 (d, J = 7.5 Hz, 2H), 2.68 (hept, J = 7.6 Hz, 1H), 2.22 - 2.13 (m, 2H), 2.04 - 1.94 (m, 1H), 1.92 - 1.79 (m, 3H), 1.67 (d, J = 6.6 Hz, 6H). ESI-MS m / z: 431.1 [M+H] + .

[0343] Example 18: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-(2,2,2-trifluoroethyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 18)

[0344] Compound 18 was prepared as a white solid from intermediate Al 4 using the method described in Compound 1.

[0345] 1 H NMR (600 MHz, Methanol-d4) δ 9.78 (s, 1H), 8.69 (s, 1H), 8.30 (d, J = 6.5 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.14 (dd, J = 8.3, 1.5 Hz, 1H), 6.61 (s, 1H), 5.58 (q, J = 8.5 Hz, 2H), 4.74 (s, 2H), 4.33 (s, 2H), 3.08 (d, J = 7.5 Hz, 2H), 2.67 (hept, J = 7.7 Hz, 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] + .

[0346] Example 19: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-(2,2-difluoroethyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 19)

[0347] Compound 19 was prepared as a white solid from intermediate Al 5 using the method described in Compound 1.

[0348] 1H NMR (500 MHz, Methanol-d4) δ 9.54 - 9.49 (m, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.72 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.06 (dd, J = 8.1, 1.5 Hz, 1H), 6.49 - 6.16 (m, 2H), 4.94 (td, J = 14.5, 3.7 Hz, 2H), 4.71 (s, 2H), 3.86 (s, 2H), 2.62 (d, J = 7.3 Hz, 2H), 2.49 (hept, J = 7.6 Hz, 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] + .

[0349] Example 20: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-(methyl-d3)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 20)

[0350] Compound 20 was prepared as a white solid from intermediate Al6 using the method described in Compound 1.

[0351] 1 H NMR (500 MHz, Methanol-d4) δ 9.45 (d, J = 1.2 Hz, 1H), 8.36 (d, J = 6.2 Hz, 1H), 7.60 (dd, J = 6.2, 1.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.29 (d, J = 0.9 Hz, 1H), 4.69 (s, 2H), 3.84 (s, 2H), 2.64 - 2.56 (m, 2H), 2.48 (hept, J = 7.7 Hz, 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] + .

[0352] Example 21: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 21)

[0353] Using the method described in compound 1, compound 22 was prepared from intermediate Al l as a white solid.

[0354] 1 H NMR (500 MHz, Methanol-d4) δ 9.57 (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, 1.5 Hz, 1H), 6.64 (s, 1H), 4.80 (s, 2H), 4.52 (s, 3H), 4.36 (s, 2H), 3.09 (d, J = 7.5 Hz, 2H), 2.68 (hept, J = 7.7 Hz, 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] + .

[0355] Example 22: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-2-ethyl-2H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 22)

[0356] Using the method described in compound 1, compound 22 was prepared from intermediate Al l as a white solid.

[0357] 1 H NMR (500 MHz, Methanol-d4) δ 9.57 (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, 1.5 Hz, 1H), 6.64 (s, 1H), 4.80 (s, 2H), 4.52 (s, 3H), 4.36 (s, 2H), 3.09 (d, J = 7.5 Hz, 2H), 2.68 (hept, J = 7.7 Hz, 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] + .

[0358] Example 23: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-2-isopropyl-2H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 23)

[0359] Compound 23 was prepared as a white solid from intermediate Al 3 using the method described in Compound 1.

[0360] 1 H NMR (500 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.20 (dd, J = 8.2, 1.5 Hz, 1H), 6.65 (s, 1H), 5.56 (hept, J = 6.4 Hz, 1H), 4.80 (s, 2H), 4.36 (s, 2H), 3.10 (d, J = 7.5 Hz, 2H), 2.69 (hept, J = 7.8 Hz, 1H), 2.17 - 2.13 (m, 1H), 2.07 - 2.01 (m, 2H), 1.92 - 1.81 (m, 3H), 1.67 (d, J = 6.6 Hz, 6H). ESI-MS m / z: 431.1 [M+H] + .

[0361] Example 24: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l,7-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 24)

[0362] Compound 24 was prepared as a white solid from intermediate Al 7 using the method described in Compound 1.

[0363] 1H NMR (500 MHz, Methanol-d4) δ 9.33 (s, 1H), 8.11 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.31 (s, 1H), 4.69 (s, 2H), 4.36 (s, 3H), 3.86 (s, 2H), 2.76 (s, 3H), 2.63 (d, J = 7.3 Hz, 2H), 2.50 (hept, J = 7.7 Hz, 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] + .

[0364] Example 26: Synthesis of N-((2-((isobutylamino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 26)

[0365] Compound 26 was prepared as a white solid from intermediate 3-2 and isobutylamine using the method described in compound 3.

[0366] 1 H NMR (500 MHz, Methanol-d4) δ 9.33 (s, 1H), 8.11 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.31 (s, 1H), 4.69 (s, 2H), 4.36 (s, 3H), 3.86 (s, 2H), 2.76 (s, 3H), 2.63 (d, J = 7.3 Hz, 2H), 2.50 (hept, J = 7.7 Hz, 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] + .

[0367] Example 27: Synthesis of l-methyl-N-((2-((neopentylamino)methyl)-lH-indol-6-yl)methyl)- lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 27)

[0368] Compound 27 was prepared as a white solid from intermediate 3-2 and neopentylamine using the method described in compound 3.

[0369] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.62 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.29 (d, J = 1.0 Hz, 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] + .

[0370] Example 28: Synthesis of N-((2-(((cyclopropylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 28)

[0371] Compound 28 was prepared as a white solid from intermediate 3-2 and cyclopropylmethylamine using the method described in compound 3.

[0372] 1 H NMR (600 MHz, Methanol-d4) δ 9.46 (s, 1H), 8.38 (d, J = 6.1 Hz, 1H), 7.63 (dd, J = 6.1, 1.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.31 (s, 1H), 4.69 (s, 2H), 4.12 (s, 3H), 3.92 (s, 2H), 2.46 (d, J = 7.0 Hz, 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] + .

[0373] Example 29: Synthesis of N-((2-(((cyclopentylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 29)

[0374] Compound 29 was prepared as a white solid from intermediate 3-2 and cyclopentylmethylamine using the method described in compound 3.

[0375] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 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 = 7.2 Hz, 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] + .

[0376] Example 30: Synthesis of N-((2-(((Cyclohexylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 30)

[0377] Compound 30 was prepared as a white solid from intermediate 3-2 and cyclohexylmethylamine using the method described in compound 3.

[0378] 1 H NMR (600 MHz, Methanol-d4) δ 9.71 (s, 1H), 8.59 (d, J = 6.9 Hz, 1H), 8.25 (d, J = 6.9 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.46 (s, 1H), 7.14 (dd, J = 8.2, 1.5 Hz, 1H), 6.62 (s, 1H), 4.74 (s, 2H), 4.36 (s, 2H), 4.31 (s, 3H), 2.88 (d, J = 7.0 Hz, 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] + .

[0379] Example 31: Synthesis of N-((2-((Benzylamino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 31)

[0380] Compound 31 was prepared as a white solid from intermediate 3-2 and benzylamine using the method described in compound 3.

[0381] 1 H NMR (600 MHz, DMSO-d6) δ 10.90 (d, J = 2.2 Hz, 1H), 9.43 (s, 1H), 9.08 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.3 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 6.2 Hz, 3H), 7.30 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.1 Hz, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 4.57 (d, J = 6.3 Hz, 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] + .

[0382] Example 32: Synthesis of l-methyl-N-((2-((((l-methylcyclopropyl)methyl)amino)methyl)-lH-indol-6-yl)methyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 32)

[0383] Compound 32 was prepared as a white solid from intermediate 3-2 and (l-methylcyclopropyl)methanamine hydrochloride using the method described in compound 3.

[0384] 1 H NMR (500 MHz, Methanol-d4) δ 9.47 (s, 1H), 8.38 (d, J = 5.8 Hz, 1H), 7.63 (d, J = 6.0 Hz, 1H), 7.43 (dd, J = 8.1, 0.7 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 0.9 Hz, 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] + .

[0385] Example 33: Synthesis of l-methyl-N-((2-(((oxetan-2-ylmethyl)amino)methyl)-lH- indol-6-yl)methyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 33)

[0386] Compound 33 was prepared as a white solid from intermediate 3-2 and oxetan-2- ylmethanamine using the method described in compound 3.

[0387] 1 H NMR (500 MHz, DMSO-d6) δ 10.87 (d, J = 2.2 Hz, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.75 (dd, J = 6.1, 1.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.26 - 6.16 (m, 1H), 4.82 - 4.69 (m, 1H), 4.56 (d, J = 6.3 Hz, 2H), 4.47 (td, J = 7.8, 5.8 Hz, 1H), 4.36 (dt, J = 9.0, 5.8 Hz, 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, 7.0 Hz, 1H). ESI-MS m / z: 405.0 [M+H] + .

[0388] Example 34: Synthesis of N-((2-((((l-hydroxycyclobutyl)methyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 34)

[0389] Compound 34 was prepared as a white solid from intermediate 3-2 and l- (aminomethyl)cyclobutanol using the method described in compound 3.

[0390] 1H NMR (500 MHz, Methanol-d4) δ 9.46 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (dd, J = 8.2, 0.7 Hz, 1H), 7.37 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.31 (d, J = 0.9 Hz, 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] + .

[0391] Example 35: Synthesis of l-methyl-N-((2-((((3-methylcyclobutyl)methyl)amino)methyl)-lH-indol-6-yl)methyl)-l-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 35)

[0392] Compound 35 was prepared as a white solid from intermediate 3-2 and (3- methylcyclobutyl)methanamine using the method described in compound 3.

[0393] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (dd, J = 8.2, 0.7 Hz, 1H), 7.37 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.31 (d, J = 0.9 Hz, 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] + .

[0394] Example 36: Synthesis of N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 36)

[0395] Compound 36 was prepared as a white solid from intermediate 3-2 and (3,3- difluorocyclobutyl)methanamine hydrochloride using the method described in Compound 3.

[0396] 1 H NMR (500 MHz, Methanol-d4) d 9.47 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.1, 1.1 Hz, 1H), 7.44 (dd, J = 8.1, 0.7 Hz, 1H), 7.37 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.31 (d, J = 0.8 Hz, 1H), 4.70 (s, 2H), 4.13 (s, 3H), 3.88 (s, 2H), 2.70 (d, J = 7.1 Hz, 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] + .

[0397] Example 37: Synthesis of N-((2-((((3-fluorobicyclo[l.l.l]pentan-l-yl)methyl)amino)methyl)- lH-indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 37)

[0398] Compound 37 was prepared as a white solid from intermediate 3-2 and (3-fluorobicyclo[l.l.l]pentan-l-yl)methanamine hydrochloride using the method described in Compound 3.

[0399] 1H NMR (500 MHz, Methanol-d4) δ 9.47 (s, 1H), 8.38 (d, J = 6.1 Hz, 1H), 7.64 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (dd, J = 8.1, 0.7 Hz, 1H), 7.37 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 0.9 Hz, 1H), 4.70 (s, 2H), 4.13 (s, 3H), 3.89 (s, 2H), 2.85 (s, 2H), 1.95 (d, J = 2.6 Hz, 6H). ESI-MS m / z: 433.1 [M+H] + .

[0400] 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)

[0401] Compound 38 was prepared as a white solid from intermediate 3-2 and 1- (aminomethyl)cyclopentanol hydrochloride salt using the method described in compound 3.

[0402] 1 H NMR (500 MHz, DMSO-d6) δ 10.86 - 10.75 (m, 1H), 9.43 (s, 1H), 9.05 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (dt, J = 1.6, 0.8 Hz, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.18 (d, J = 1.8 Hz, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.51 (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] + .

[0403] Example 39: Synthesis of N-((2-(((bicyclo[2.2.1]heptan-5-en-2-ylmethyl)amino)methyl)- 1H-indol-6-yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 39)

[0404] Compound 39 was prepared as a white solid from intermediate 3-2 and 5-norbornene-2- methylamine using the method described in compound 3.

[0405] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (d, J = 1.3 Hz, 1H), 8.37 (d, J = 6.2 Hz, 1H), 7.62 (dd, J = 6.2, 1.2 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.37 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.29 (d, J = 0.9 Hz, 1H), 6.06 (dd, J = 5.8, 3.1 Hz, 1H), 5.84 (dd, J = 5.8, 2.9 Hz, 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] + .

[0406] Example 40: Synthesis of N-((2-(((((3r,5r,7r)-adamantan-l-yl)methyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 40)

[0407] Compound 40 was prepared as a white solid from intermediate 3-2 and l-aminomethyladamantane using the method described in compound 3.

[0408] 1H NMR (500 MHz, Methanol-d4) δ 9.46 (d, J = 1.2 Hz, 1H), 8.37 (d, J = 6.2 Hz, 1H), 7.61 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.29 (d, J = 0.9 Hz, 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 = 2.8 Hz, 6H). ESI-MS m / z: 483.0 [M+H] + .

[0409] Example 41: Synthesis of N-((2-((cyclopropylamino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 41)

[0410] Compound 41 was prepared as a white solid from intermediate 3-2 and cyclopropylamine using the method described in compound 3.

[0411] 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (d, J = 2.0 Hz, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.05 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.1 Hz, 1H), 7.76 (dd, J = 6.0, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.33 - 7.31 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 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, 3.6 Hz, 1H), 0.36 - 0.30 (m, 2H), 0.27 - 0.21 (m, 2H). ESI-MS m / z: 375.0 [M+H] + .

[0412] Example 42: Synthesis of N-((2-((cyclobutylamino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 42)

[0413] Using the method described in compound 3, compound 43 was prepared from intermediate 3-2 and cyclopentylamine as a white solid.

[0414] 1 H NMR (500 MHz, Methanol-d4) δ 9.49 - 9.43 (m, 1H), 8.37 (d, J = 6.2 Hz, 1H), 7.61 (dd, J = 6.2, 1.2 Hz, 1H), 7.43 (dd, J = 8.1, 0.7 Hz, 1H), 7.36 (dt, J = 1.6, 0.8 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.29 (q, J = 0.8 Hz, 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] + .

[0415] Example 43: Synthesis of N-((2-((cyclopentylamino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 43)

[0416] Using the method described in compound 3, compound 43 was prepared from intermediate 3-2 and cyclopentylamine as a white solid.

[0417] 1 H NMR (500 MHz, Methanol-d4) δ 9.49 - 9.43 (m, 1H), 8.37 (d, J = 6.2 Hz, 1H), 7.61 (dd, J = 6.2, 1.2 Hz, 1H), 7.43 (dd, J = 8.1, 0.7 Hz, 1H), 7.36 (dt, J = 1.6, 0.8 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.29 (q, J = 0.8 Hz, 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] + .

[0418] Example 44: Synthesis of N-((2-((cyclohexylamino)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 44)

[0419] Compound 44 was prepared as a white solid from intermediate 3-2 and cyclohexylamine using the method described in compound 3.

[0420] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (dd, J = 8.1, 0.7 Hz, 1H), 7.37 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 0.9 Hz, 1H), 4.70 (s, 2H), 4.13 (s, 3H), 3.93 - 3.88 (m, 2H), 2.46 (tt, J = 10.6, 3.8 Hz, 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] + .

[0421] Example 45: Synthesis of N-((2-((bicyclo[l.l.l]pentan-l-ylamino)methyl)-lH-indol-6-yl)methyl)- 1 -methyl- 1 H-pyrazolo [4,3 -c]pyridine-3 -carboxamide (Compound 45)

[0422] Compound 45 was prepared as a white solid from intermediate 3-2 and bicyclo[l.l.l]pentan-l-amine hydrochloride using the method described in compound 3.

[0423] 1H NMR (500 MHz, Methanol-d4) δ 9.46 (s, 1H), 8.38 (d, J = 6.1 Hz, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.42 (dd, J = 8.1, 0.7 Hz, 1H), 7.36 (dt, J = 1.6, 0.8 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.29 (d, J = 0.9 Hz, 1H), 4.69 (s, 2H), 4.12 (s, 3H), 3.86 (d, J = 0.8 Hz, 2H), 2.36 (s, 1H), 1.79 (s, 6H). ESI-MS m / z: 400.9 [M+H] + .

[0424] Example 46: Synthesis of N-((2-((adamantan-l-ylamino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 46)

[0425] Compound 46 was prepared as a white solid from intermediate 3-2 and adamantanamine using the method described in compound 3.

[0426] 1 H NMR (600 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.42 (s, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.36 - 7.31 (m, 2H), 6.96 (dd, J = 8.1, 1.5 Hz, 1H), 6.17 (s, 1H), 4.55 (d, J = 6.2 Hz, 2H), 4.13 (s, 3H), 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] + .

[0427] Example 47: Synthesis of N-((2-(((cyclobutylmethyl)(methyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 47)

[0428] Compound 47 was prepared as a white solid from intermediate 3-2 and l-cyclobutyl-N- methylmethanamine hydrochloride using the method described in compound 3.

[0429] 1 H NMR (500 MHz, Methanol-d4) δ 9.45 (s, 1H), 8.37 (d, J = 6.1 Hz, 1H), 7.61 (dd, J = 6.1, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.32 - 6.25 (m, 1H), 4.69 (s, 2H), 4.11 (s, 3H), 3.62 (s, 2H), 2.58 (hept, J = 7.7 Hz, 1H), 2.44 (d, J = 7.0 Hz, 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] + .

[0430] Example 48: Synthesis of l-methyl-N-((2-(piperidin-l-ylmethyl)-lH-indol-6- yl)methyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 48)

[0431] Compound 48 was prepared as a white solid from intermediate 3-2 and piperidine using the method described in compound 3.

[0432] 1 H NMR (500 MHz, Methanol-d4) δ 9.45 (s, 1H), 8.37 (d, J = 6.1 Hz, 1H), 7.61 (dd, J = 6.1, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.32 - 6.25 (m, 1H), 4.69 (s, 2H), 4.11 (s, 3H), 3.62 (s, 2H), 2.58 (hept, J = 7.7 Hz, 1H), 2.44 (d, J = 7.0 Hz, 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] + .

[0433] Example 49: Synthesis of N-((2-((4-fluoropiperidin-l-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 49)

[0434] Compound 49 was prepared as a white solid from intermediate 3-2 and 4-fluoropiperidine using the method described in compound 3.

[0435] 1 H NMR (600 MHz, DMSO-d6) δ 10.93 (d, J = 2.2 Hz, 1H), 9.45 - 9.38 (m, 1H), 9.08 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 4.66 (dtt, J = 49.0, 7.4, 3.6 Hz, 1H), 4.55 (d, J = 6.1 Hz, 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] + .

[0436] Example 50: Synthesis of N-((2-((4,4-difluoropiperidin-l-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 50)

[0437] Compound 50 was prepared as a white solid from intermediate 3-2 and 4,4- difluoropiperidine using the method described in compound 3.

[0438] 1 H NMR (600 MHz, DMSO-d6) δ 10.93 (d, J = 2.2 Hz, 1H), 9.45 - 9.38 (m, 1H), 9.08 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 4.66 (dtt, J = 49.0, 7.4, 3.6 Hz, 1H), 4.55 (d, J = 6.1 Hz, 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] + .

[0439] Example 51: Synthesis of N-((2-(((4,4-dimethylcyclohexyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 51)

[0440] Compound 51 was prepared as a white solid from intermediate 3-2 and 4,4- dimethylpiperidine using the method described in compound 3.

[0441] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (d, J = 1.2 Hz, 1H), 8.37 (d, J = 6.1 Hz, 1H), 7.62 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 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 = 5.7 Hz, 4H), 0.90 (s, 6H). ESI-MS m / z: 431.2 [M+H] + .

[0442] Example 52: Synthesis of N-((2-((6-azaspiro[2.5]octan-6-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 52)

[0443] Compound 52 was prepared as a white solid from intermediate 3-2 and 6- azaspiro[2.5]octane hydrochloride using the method described in compound 3.

[0444] 1H NMR (500 MHz, DMSO-d6) δ 10.92 (d, J = 2.1 Hz, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.2 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.35 - 7.32 (m, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 (dd, J = 2.0, 0.9 Hz, 1H), 4.56 (d, J = 6.3 Hz, 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] + .

[0445] Example 53: Synthesis of l-methyl-N-((2-(morpholinomethyl)-lH-indol-6-yl)methyl)- lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 53)

[0446] Compound 53 was prepared as a white solid from intermediate 3-2 and morpholine using the method described in compound 3.

[0447] 1 H NMR (600 MHz, DMSO-d6) δ 10.95 (d, J = 2.2 Hz, 1H), 9.45 - 9.36 (m, 1H), 9.08 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.13 (s, 3H), 3.58 - 3.55 (m, 6H), 2.36 (t, J = 4.6 Hz, 4H). ESI-MS m / z: 405.0 [M+H] + .

[0448] Example 54: Synthesis of N-((2-((2-azabicyclo[2.2.1]heptan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 54)

[0449] Compound 54 was prepared as a white solid from intermediate 3-2 and 2-azabicyclo[2.2.1]heptane hydrochloride salt using the method described in compound 3.

[0450] 1 H NMR (500 MHz, Methanol-d4) d 9.46 (s, 1H), 8.38 (d, J = 6.1 Hz, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.31 (s, 1H), 4.69 (s, 2H), 4.12 (s, 3H), 3.82 - 3.70 (m, 2H), 3.29 (d, J = 2.6 Hz, 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] + .

[0451] Example 55: Synthesis of N-((2-((2-azabicyclo[2.2.2]octan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 55)

[0452] Compound 55 was prepared as a white solid from intermediate 3-2 and 2-azabicyclo[2.2.2]octane hydrochloride salt using the method described in compound 3.

[0453] 1H NMR (600 MHz, DMSO-d6) δ 10.85 (d, J = 2.2 Hz, 1H), 9.42 (s, 1H), 9.07 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 4.13 (s, 3H), 3.70 (s, 2H), 2.64 (d, J = 2.3 Hz, 2H), 2.05 - 1.93 (m, 1H), 1.89 (tt, J = 12.4, 4.0 Hz, 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] + .

[0454] Example 56: Synthesis of l-methyl-N-((2-(pyrrolidin-l-ylmethyl)-lH-indol-6- yl)methyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 56)

[0455] Compound 56 was prepared as a white solid from intermediate 3-2 and tetrahydropyrrole using the method described in compound 3.

[0456] 1 H NMR (500 MHz, Methanol-d4) δ 9.46 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.1, 1.2 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.38 (dt, J = 1.6, 0.8 Hz, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.31 (d, J = 0.9 Hz, 1H), 4.70 (s, 2H), 4.13 (s, 3H), 3.77 (s, 2H), 2.65 - 2.55 (m, 4H), 1.80 (p, J = 3.2 Hz, 4H). ESI-MS m / z: 389.0 [M+H] + .

[0457] Example 57: Synthesis of N-((2-((2-azabicyclo[2.1.1]hexan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 57)

[0458] Compound 57 was prepared as a white solid from intermediate 3-2 and 2-azabicyclo[2.1.1]hexane hydrochloride using the method described in compound 3.

[0459] 1 H NMR (500 MHz, DMSO-d6) δ 10.99 - 10.90 (m, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.35 - 7.32 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 (dd, J = 2.0, 1.0 Hz, 1H), 4.56 (d, J = 6.3 Hz, 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] + .

[0460] Example 58: Synthesis of N-((2-((2,2-dimethylpyrrolidin-l-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 58)

[0461] Compound 58 was prepared as a white solid from intermediate 3-2 and 2,2- dimethylpyrrolidine using the method described in compound 3.

[0462] 1 H NMR (500 MHz, DMSO-d6) δ 10.99 - 10.90 (m, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.35 - 7.32 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 (dd, J = 2.0, 1.0 Hz, 1H), 4.56 (d, J = 6.3 Hz, 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] + .

[0463] Example 59: Synthesis of N-((2-((3,3-dimethylpyrrolidin-l-yl)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 59)

[0464] Compound 59 was prepared as a white solid from intermediate 3-2 and 3,3- dimethylpyrrolidine hydrochloride salt using the method described in compound 3.

[0465] 1 H NMR (500 MHz, Methanol-d4) δ 9.48 (s, 1H), 8.40 (d, J = 6.1 Hz, 1H), 7.66 (dd, J = 6.2, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 0.9 Hz, 1H), 4.71 (s, 2H), 4.14 (s, 3H), 3.74 (s, 2H), 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] + .

[0466] Example 60: Synthesis of N-((2-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 60)

[0467] Compound 60 was prepared as a white solid from intermediate 3-2 and 3- azabicyclo[3.1.0]hexane hydrochloride salt using the method described in compound 3.

[0468] 1H 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] + .

[0469] 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)

[0470] 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.

[0471] 1 H 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]+ .

[0472] Example 62: Synthesis of N-((2-((5-azaspiro[2.4]heptan-5-yl)methyl)-1H-indol-6- yl)methyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 62)

[0473] Compound 62 was prepared as a white solid from intermediate 3-2 and 5-azaspiro[2.4]heptane hydrochloride salt using the method described in compound 3.

[0474] 1 H NMR (500 MHz, DMSO-d6) d 11.00 - 10.88 (m, 1H), 9.43 (d, J = 1.2 Hz, 1H), 8.97 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.74 (dd, J = 6.0, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.33 (dt, J = 1.6, 0.8 Hz, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.20 (dd, J = 2.1, 1.0 Hz, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.13 (s, 3H), 3.68 (s, 2H), 2.67 (t, J = 6.9 Hz, 2H), 2.43 (s, 2H), 1.73 (t, J = 6.8 Hz, 2H), 0.47 (dt, J = 10.0, 2.0 Hz, 4H). ESI-MS m / z: 415.0 [M+H] + .

[0475] Example 63: Synthesis of N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-indol-6-yl)methyl)- 1-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 63)

[0476] Compound 63 was prepared as a white solid from intermediate 3-2 and 6-azaspiro[3.4]octane hydrochloride salt using the method described in compound 3.

[0477] 1H NMR (600 MHz, DMSO-d6) δ 10.92 (d, J = 2.1 Hz, 1H), 9.42 (s, 1H), 9.07 (t, J = 6.3 Hz, 1H), 8.44 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.23 - 6.14 (m, 1H), 4.55 (d, J = 6.2 Hz, 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 = 7.0 Hz, 2H), 1.77 - 1.66 (m, 2H). ESI-MS m / z: 429.0 [M+H] + .

[0478] Example 64: Synthesis of N-((2-((3,3-dimethylazetidin-l-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 64)

[0479] Compound 64 was prepared as a white solid using the method described in Compound 3 from intermediate 3-2 and 3,3-dimethylazetidine hydrochloride.

[0480] 1 H NMR (500 MHz, DMSO-d6) δ 10.86 (d, J = 2.0 Hz, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.31 (dt, J = 1.6, 0.8 Hz, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.17 (dd, J = 2.1, 1.0 Hz, 1H), 4.55 (d, J = 6.3 Hz, 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] + .

[0481] Example 65: Synthesis of N-((2-((2-azaspiro[3.3]heptan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 65)

[0482] Compound 65 was prepared as a white solid from intermediate 3-2 and 2-azaspiro[3.3]heptane hydrochloride salt using the method described in compound 3.

[0483] 1 H NMR (500 MHz, DMSO-d6) d 10.89 (d, J = 2.0 Hz, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.33 - 7.28 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.16 (dd, J = 2.1, 0.9 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.56 (s, 2H), 3.09 (s, 4H), 2.01 (t, J = 7.6 Hz, 4H), 1.79 - 1.68 (m, 2H). ESI-MS m / z: 415.0 [M+H] + .

[0484] Example 66: Synthesis of N-((2-((6-fluoro-2-azaspiro[3.3]heptan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 66)

[0485] Compound 66 was prepared as a white solid from intermediate 3-2 and 6-fluoro-2-azaspiro[3.3]heptane trifluoroacetate salt using the method described in compound 3.

[0486] 1H NMR (500 MHz, DMSO-d6) δ 10.90 (d, J = 2.0 Hz, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.33 - 7.27 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.17 (dd, J = 2.0, 1.0 Hz, 1H), 4.91 (dp, J = 56.0, 6.7 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.57 (s, 2H), 3.12 (d, J = 9.1 Hz, 4H), 2.49 - 2.41 (m, 2H), 2.25 - 2.12 (m, 2H). ESI-MS m / z: 433.1 [M+H] + .

[0487] Example 67: Synthesis of N-((2-((6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 67)

[0488] Compound 67 was prepared as a white solid using the method described in compound 3 from intermediate 3-2 and 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate salt.

[0489] 1 H NMR (500 MHz, DMSO-d6) δ 10.92 (d, J = 2.1 Hz, 1H), 9.42 (s, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.18 (dd, J = 2.1, 1.0 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.61 (s, 2H), 3.21 (s, 4H), 2.67 (t, J = 12.6 Hz, 4H). ESI-MS m / z: 451.0 [M+H] + .

[0490] Example 68: Synthesis of N-((2-((2-azaspiro[3.5]nonan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 68)

[0491] Compound 68 was prepared as a white solid from intermediate 3-2 and 2-azaspiro[3.5]nonane hydrochloride using the method described in compound 3.

[0492] 1 H NMR (500 MHz, DMSO-d6) δ 10.85 - 10.76 (m, 1H), 9.43 (d, J = 1.2 Hz, 1H), 8.96 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.74 (dd, J = 6.1, 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.33 - 7.30 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.18 (dd, J = 2.0, 1.0 Hz, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.13 (s, 3H), 3.63 (s, 2H), 2.90 (s, 4H), 1.54 (t, J = 5.4 Hz, 4H), 1.39 - 1.27 (m, 6H). ESI-MS m / z: 443.0 [M+H] + .

[0493] Example 69: Synthesis of N-((2-((cyclobutylmethyl)amino)methyl)-l-methyl-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 69)

[0494] Compound 69 was prepared as a white solid from intermediate B2 and intermediate Bl using the method described in compound 3.

[0495] 1H NMR (600 MHz, DMSO-d6) δ 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.1, 1.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.04 (dd, J = 8.1, 1.4 Hz, 1H), 6.27 (s, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.82 (s, 2H), 3.70 (s, 3H), 3.33 (s, 1H), 2.55 (d, J = 7.1 Hz, 2H), 2.40 (hept, J = 7.6 Hz, 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] + .

[0496] Example 70: Synthesis of N-((2-((cyclobutylmethyl)amino)methyl)-lH- benzo[d]imidazol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 70)

[0497] Step a: Synthesis of intermediate 70-1

[0498] 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), then a solution of 3,4-diaminobenzonitrile (1.0 g, 7.51 mmol) in DMF (2 mL) was added, and stirred at room temperature overnight. TLC detection showed that the starting material was completely consumed. After the reaction solution was concentrated under reduced pressure, it was 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, yield 91%). Without purification, it was directly used in the next step reaction. ESI-MS m / z: 290.9 [M+H] + .

[0499] Step b: Synthesis of intermediate 70-2

[0500] Intermediate 70-1 (2.0 g, 6.83 mmol) was dissolved in acetic acid (10 mL), and the reaction solution was heated to 70 °C and stirred for 3 hours. TLC detection showed that the starting material was completely consumed. The reaction solution was concentrated under reduced pressure, and was separated and purified by column chromatography to prepare a light gray solid (1.5 g, yield 80%).

[0501] 1H NMR (400 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.58 (s, 1H), 7.49 (dd, J = 8.3, 1.5 Hz, 1H), 5.97 (t, J = 6.1 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 1.45 (s, 9H). ESI-MS m / z: 272.9 [M+H] + .

[0502] Step c: Synthesis of intermediate 70-3

[0503] The synthesis of intermediate 70-3 was performed according to the synthetic procedure of intermediate Bl, by replacing intermediate Bl-2 with intermediate 70-2. It was used in the next step without purification.

[0504] Step d: Synthesis of intermediate 70-4

[0505] The synthesis of intermediate 70-4 was performed according to the synthetic procedure of intermediate 3-1, by replacing intermediate Bl with intermediate 70-3. It was obtained as a yellow foamy solid.

[0506] 1 H NMR (400 MHz, Chloroform-d) δ 9.64 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 6.1 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.42 (t, J = 5.9 Hz, 1H), 7.26 - 7.19 (m, 2H), 5.95 (s, 1H), 4.73 (d, J = 5.9 Hz, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.01 (s, 3H), 1.41 (s, 9H). ESI-MS m / z: 436.2 [M+H] + .

[0507] Step e: Synthesis of intermediate 70-5

[0508] The synthesis of intermediate 70-5 was performed according to the synthetic procedure of intermediate A2-2, from intermediate 70-4. ESI-MS m / z: 335.9 [M+H] + .

[0509] Step f: Synthesis of compound 70

[0510] Intermediate 70-5 (50.0 mg, 134.84 pmol) was dissolved in ethanol (6 mL), DIEA (70.5 pL, 404.51 pmol) and cyclobutylcarboxaldehyde (11.3 mg, 134.84 pmol) were added, and stirred at room temperature for 1 h. Then the reaction was cooled to 0 °C, NaBH4(5.1 mg, 134.84 pmol) was added, and stirring was continued at room temperature for 1 h. TLC showed that the starting material was consumed completely. Diluted with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, separated and purified to give compound 3-57 (25.0 mg, yield 46%) as a white solid.

[0511] 1 H NMR (500 MHz, Methanol-d4) d 9.47 (d, J = 1.2 Hz, 1H), 8.40 (d, J = 6.2 Hz, 1H), 7.67 (dd, J = 6.2, 1.2 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.53 - 7.49 (m, 1H), 7.31 (dd, J = 8.3, 1.6 Hz, 1H), 4.74 (s, 2H), 4.16 (s, 3H), 3.98 (s, 2H), 2.66 (d, J = 7.3 Hz, 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] + .

[0512] Example 75: Synthesis of N-((6-((cyclobutylmethyl)amino)methyl)imidazo[l,2- a]pyridin-2-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 75)

[0513] Step a: Synthesis of intermediate 75-1

[0514] 6-chloronicotinaldehyde (1.0 g, 7.06 mmol) was dissolved in DCE, cyclobutylmethylamine (1.2 g, 14.13 mmol) and acetic acid (0.2 mL) were added, stirred at room temperature for 2 h, then STAB was added in portions, and stirring was continued at room temperature for 2 h. TLC showed that the starting material was consumed completely. Quenched with saturated sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to give a light yellow oily liquid (1.0 g, yield 67%).

[0515] 1H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.2, 2.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 3.76 (s, 2H), 2.62 (d, J = 7.2 Hz, 2H), 2.46 (p, J = 7.6 Hz, 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] + .

[0516] Step b: synthesis of intermediate 75-2

[0517] Intermediate 75-1 (1.0 g, 4.84 mmol) was dissolved in THF, TEA (1.7 mL, 12.11 mmol) and tert-butyl dicarbonate (2.1 g, 9.68 mmol) were added successively, stirred at room temperature for 2 hours. TLC monitoring of the raw material was consumed completely. Diluted with water, EA extraction, saturated brine washing, anhydrous sodium sulfate drying, reduced pressure concentration, separated and purified by column chromatography to get colorless oily liquid (1.4 g, yield 92%).

[0518] 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.2, 2.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 3.76 (s, 2H), 2.62 (d, J = 7.2 Hz, 2H), 2.46 (p, J = 7.6 Hz, 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] + .

[0519] Step c: synthesis of intermediate 75-3

[0520] Pd2(dba)3(408.2 mg, 445.72 μmol) and Xphos (425.0 mg, 891.44 μmol) were placed in a Schlenk flask, replaced with argon for three times, THF (20 mL), THF solution of intermediate 75-2 (1.4 g, 4.46 mmol) and LiHMDS (1.0 M in THF, 6.7 mL) were added in turn at room temperature. After the reaction solution was heated to 70 °C, it was continuously stirred for 3 h, and TLC detection showed that the starting material was completely consumed. It was quenched by saturated sodium bicarbonate, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography (PE / EA = 1 / 1) to give a yellow oily liquid (1.2 g, yield 92%). ESI-MS m / z: 291.9 [M+H] + .

[0521] Step d: synthesis of intermediate 75-4

[0522] Intermediate 75-3 (1.3 g, 4.41 mmol) was dissolved in DME, 1,3-dichloroacetone was added, and the temperature was raised to 80 °C, and stirred overnight. TLC detection showed that the starting material was completely consumed. It was neutralized with saturated sodium bicarbonate, extracted with EA, washed with saturated brine, concentrated under reduced pressure, and then separated and purified by column chromatography to give a yellow oily liquid (786.8 mg, yield 49%). ESI-MS m / z: 364.0, 366.0 [M+H] + .

[0523] Step e: synthesis of intermediate 75-5

[0524] Intermediate 75-4 (786.8 mg, 2.16 mmol) was dissolved in dioxane (14 mL), and then ammonia water (14 mL) was added to seal the tube, and stirred at 80 °C for 3 h. TLC detection showed that the starting material was completely consumed. The reaction solution was concentrated under reduced pressure, and then separated and purified by column chromatography to give a yellow oily liquid (551.1 mg, yield 74%). ESI-MS m / z: 345.0 [M+H] + .

[0525] Step f: synthesis of intermediate 75-6

[0526] Referring to the synthesis method of intermediate 3-1, intermediate 75-6 was obtained from intermediate A2 and intermediate 75-5 as a brown solid. ESI-MS m / z: 504.0 [M+H] + .

[0527] Step g: synthesis of compound 75

[0528] Referring to the synthesis method of intermediate A2-2, compound 75 was obtained from intermediate 75-6 as a white solid.

[0529] 1 H NMR (500 MHz, Methanol-d4) δ 9.45 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 6.2 Hz, 1H), 8.29 (dd, J = 1.8, 1.0 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.66 (dd, J = 6.2, 1.2 Hz, 1H), 7.45 (dt, J = 9.2, 0.8 Hz, 1H), 7.32 (dd, J = 9.3, 1.7 Hz, 1H), 4.78 - 4.73 (m, 2H), 4.16 (s, 3H), 3.73 - 3.69 (m, 2H), 2.60 (d, J = 7.3 Hz, 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] + .

[0530] Example 79: Synthesis of N-((6-((cyclopentylamino)methyl)imidazo[l,2- a]pyridin-2-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 79)

[0531] Using the method described in compound 3, replacing cyclobutylmethylamine with cyclopentylamine, white solid compound 79 was prepared.

[0532] 1 H NMR (600 MHz, Methanol-d4) δ 9.43 (d, J = 1.2 Hz, 1H), 8.37 (d, J = 6.2 Hz, 1H), 8.32 - 8.26 (m, 1H), 7.78 - 7.73 (m, 1H), 7.63 (dd, J = 6.2, 1.2 Hz, 1H), 7.43 (d, J = 9.3 Hz, 1H), 7.31 (dd, J = 9.3, 1.7 Hz, 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] + .

[0533] Example 80: Synthesis of N-((2-((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-5-fluoro-l-methyl-lH-indazole-3-carboxamide (Compound 80)

[0534] Compound 80 was prepared as a white solid from 5-fluoro-l-methyl-lH-indazole-3- carboxylic acid using the method described in Compound 1.

[0535] 1 H NMR (500 MHz, Methanol-d4) δ 7.87 - 7.79 (m, 1H), 7.57 (dd, J = 9.1, 4.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.37 - 7.34 (m, 1H), 7.24 (td, J = 9.1, 2.5 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (d, J = 0.9 Hz, 1H), 4.67 (s, 2H), 4.08 (s, 3H), 3.85 (s, 2H), 2.61 (d, J = 7.3 Hz, 2H), 2.49 (hept, J = 7.7 Hz, 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] + .

[0536] Example 81: Synthesis of N-((2-(((2-fluoro-2-methylpropyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 81)

[0537] Compound 81 was prepared as a white solid from intermediate 3-2 and 2-fluoro-2- methylpropan-1-amine hydrochloride using the method described in Compound 3.

[0538] 1H NMR (800 MHz, Methanol-d4) δ 9.48 - 9.42 (m, 1H), 8.37 (d, J = 6.2 Hz, 1H), 7.62 (dd, J = 6.2, 1.3 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.29 (d, J = 0.9 Hz, 1H), 4.69 (s, 2H), 4.12 (s, 3H), 3.91 (s, 2H), 2.69 (d, J = 19.8 Hz, 2H), 1.33 (d, J = 21.3 Hz, 6H). ESI-MS m / z: 409.1 [M+H] + .

[0539] Example 82: Synthesis of N-((2-(((3,3-difluorocyclopentyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 82)

[0540] Compound 82 was prepared as a white solid from intermediate 3-2 and 3,3- difluorocyclopentylamine hydrochloride using the method described in compound 3.

[0541] 1 H NMR (800 MHz, Methanol-d4) δ 9.46 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.63 (dd, J = 6.1, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.32 (d, J = 1.0 Hz, 1H), 4.70 (s, 2H), 4.12 (s, 3H), 3.87 (d, J = 0.8 Hz, 2H), 3.26 (p, J = 7.7 Hz, 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] + .

[0542] Example 83: Synthesis of N-((2-((3-fluoropyrrolidin-l-yl)methyl)-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 83)

[0543] Compound 83 was prepared as a white solid from intermediate 3-2 and 3-fluoropyrrolidine hydrochloride using the method described in compound 3.

[0544] 1 H NMR (600 MHz, DMSO-d6) δ 10.99 (d, J = 2.1 Hz, 1H), 9.42 (d, J = 1.3 Hz, 1H), 9.08 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.2 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.27 - 6.19 (m, 1H), 5.18 (dtd, J = 55.9, 5.0, 1.8 Hz, 1H), 4.55 (d, J = 6.3 Hz, 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] + .

[0545] Example 84: Synthesis of N-((2-((3,3-difluoropyrrolidin-l-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 84)

[0546] Compound 84 was prepared as a white solid from intermediate 3-2 and 3,3-difluoropyrrolidine hydrochloride using the method described in compound 3.

[0547] 1H NMR (600 MHz, DMSO-d6) δ 11.07 - 10.97 (m, 1H), 9.42 (d, J = 1.3 Hz, 1H), 9.09 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.3 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.00 (dd, J = 8.1, 1.5 Hz, 1H), 6.26 - 6.21 (m, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.14 (s, 3H), 3.73 (s, 2H), 2.88 (t, J = 13.3 Hz, 2H), 2.70 (t, J = 7.0 Hz, 2H), 2.23 (tt, J = 14.9, 7.0 Hz, 2H). ESI-MS m / z: 425.1 [M+H] + .

[0548] Example 85: Synthesis of N-((2-((((l-fluorocyclopropyl)methyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 85)

[0549] Compound 85 was prepared as a white solid from intermediate 3-2 and (l-fluorocyclopropyl)methanamine hydrochloride salt using the method described in compound 3.

[0550] 1 H NMR (800 MHz, DMSO-d6) δ 10.88 (d, J = 2.1 Hz, 1H), 9.42 (d, J = 1.3 Hz, 1H), 9.06 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.22 (dd, J = 2.1, 1.0 Hz, 1H), 4.56 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.88 (s, 2H), 2.85 (d, J = 20.9 Hz, 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] + .

[0551] Example 86: Synthesis of N-((2-((((l-fluorocyclobutyl)methyl)amino)methyl)-lH- indol-6-yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 86)

[0552] Compound 86 was prepared as a white solid from intermediate 3-2 and (l- fluorocyclobutyl)methanamine hydrochloride using the method described in compound 3.

[0553] 1 H NMR (800 MHz, DMSO-d6) δ 10.90 - 10.84 (m, 1H), 9.42 (d, J = 1.3 Hz, 1H), 9.07 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 1.2 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.22 (dd, J = 2.0, 1.0 Hz, 1H), 4.57 (s, 2H), 4.13 (s, 3H), 3.85 (s, 2H), 2.72 (d, J = 24.2 Hz, 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] + .

[0554] Example 87: Synthesis of N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)- 1,6-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 87)

[0555] Compound 87 was prepared as a white solid from intermediate A18 using the method described in compound 1.

[0556] H NMR (800 MHz, DMSO-d6) δ 10.90 - 10.80 (m, 1H), 9.29 (d, J = 1.2 Hz, 1H), 9.00 (t, J = 6.3 Hz, 1H), 7.57 (t, J = 1.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.34 - 7.30 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.19 (dd, J = 2.0, 1.0 Hz, 1H), 4.55 (d, J = 6.3 Hz, 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, 7.4 Hz, 1H), 1.99 - 1.93 (m, 2H), 1.81 (dq, J = 11.0, 8.5 Hz, 1H), 1.78 - 1.72 (m, 1H), 1.64 - 1.57 (m, 2H). ESI-MS m / z: 417.2 [M+H] + .

[0557] Example 88: Synthesis of N-((2-((((3-fluorobicyclo[l.l.l]pentan-l-yl)methyl)amino)methyl)-lH-indol-6-yl)methyl)-l,7-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 88)

[0558] Using the method described in compound 24, replacing cyclobutylmethylamine with (3-fluorobicyclo[l.l.l]pentan-l-yl)methylamine hydrochloride, white solid compound 88 was prepared.

[0559] 1 H NMR (800 MHz, DMSO-d6) δ 10.84 (d, J = 2.3 Hz, 1H), 9.28 (s, 1H), 8.99 (t, J = 6.3 Hz, 1H), 8.16 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 6.98 (dd, J = 8.2, 1.4 Hz, 1H), 6.20 (d, J = 1.9 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.32 (s, 3H), 3.80 (s, 2H), 2.74 (s, 2H), 2.71 (s, 3H), 1.92 (d, J = 2.7 Hz, 6H). ESI-MS m / z: 447.1 [M+H] + .

[0560] Example 89: Synthesis of N-((2-((isobutylamino)methyl)-lH-indol-6-yl)methyl)-l,7- dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 89)

[0561] Using the procedure described in compound 24, replacing cyclobutylmethylamine with isobutylamine, white solid compound 89 was prepared.

[0562] 1 H NMR (800 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.27 (s, 1H), 8.98 (t, J = 6.3 Hz, 1H), 8.15 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 4.54 (d, J = 6.2 Hz, 2H), 4.30 (s, 3H), 3.76 (s, 2H), 2.70 (s, 3H), 2.28 (d, J = 6.7 Hz, 2H), 1.64 (hept, J = 6.7 Hz, 1H), 0.83 (d, J = 6.7 Hz, 6H). ESI-MS m / z: 405.1 [M+H] + .

[0563] Example 90: Synthesis of N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-lH- indol-6-yl)methyl)-l,7-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 90)

[0564] Using the procedure described in compound 24, replacing cyclobutylmethylamine with (3,3-difluorocyclobutyl)methylamine hydrochloride, white solid compound 90 was prepared.

[0565] 1H NMR (500 MHz, DMSO-d6) δ 10.89 - 10.78 (m, 1H), 9.28 (s, 1H), 8.98 (t, J = 6.3 Hz, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.20 (dd, J = 2.0, 1.0 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 4.32 (s, 3H), 3.77 (s, 2H), 2.97 (p, J = 6.3 Hz, 1H), 2.71 (s, 3H), 1.68 (dtdd, J = 12.1, 6.7, 5.2, 1.5 Hz, 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] + .

[0566] Example 91: Synthesis of N-((2-((cyclopentylamino)methyl)-lH-indol-6-yl)methyl)- 1,7-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 91)

[0567] Using the method described in compound 24, replacing cyclobutylmethylamine with cyclopentylamine, white solid compound 91 was prepared.

[0568] 1 H NMR (500 MHz, DMSO-d6) δ 10.89 - 10.78 (m, 1H), 9.28 (s, 1H), 8.98 (t, J = 6.3 Hz, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.20 (dd, J = 2.0, 1.0 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 4.32 (s, 3H), 3.77 (s, 2H), 2.97 (p, J = 6.3 Hz, 1H), 2.71 (s, 3H), 1.68 (dtdd, J = 12.1, 6.7, 5.2, 1.5 Hz, 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] + .

[0569] Example 92: Synthesis of N-((2-((6-azaspiro[2.5]octan-6-yl)methyl)-lH-indol-6- yl)methyl)-l,7-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 92)

[0570] Using the method described in compound 24, cyclobutylmethylamine was replaced with 6-azaspiro[2.5]octane hydrochloride to afford compound 92 as a white solid.

[0571] 1 H NMR (500 MHz, DMSO-d6) δ 10.92 (d, J = 2.2 Hz, 1H), 9.28 (s, 1H), 8.99 (t, J = 6.3 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.21 (d, J = 1.9 Hz, 1H), 4.55 (d, J = 6.2 Hz, 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] + .

[0572] Example 93: Synthesis of N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-lH-indol-6- yl)methyl)-l,7-dimethyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 93)

[0573] Using the method described in compound 24, cyclobutylmethylamine was replaced with 6-azaspiro[3.4]octane hydrochloride to afford compound 93 as a white solid.

[0574] 1H NMR (600 MHz, DMSO-d6) δ 10.91 (d, J = 2.2 Hz, 1H), 9.27 (s, 1H), 8.98 (t, J = 6.3 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.34 - 7.27 (m, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.18 (dd, J = 2.1, 0.9 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 4.30 (s, 3H), 3.62 (s, 2H), 2.70 (t, J = 0.8 Hz, 3H), 2.51 (s, 2H), 2.48 - 2.46 (m, 2H), 1.94 - 1.83 (m, 4H), 1.79 (t, J = 7.0 Hz, 2H), 1.76 - 1.63 (m, 2H). ESI-MS m / z: 443.1 [M+H] + .

[0575] Example 94: Synthesis of N-((2-((2-azaspiro[4.4]nonan-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 94)

[0576] Compound 94 was prepared as a white solid from intermediate 3-2 and 2-azaspiro[4.4]nonane using the method described in compound 3.

[0577] 1 H NMR (500 MHz, DMSO-d6) δ 10.95 - 10.83 (m, 1H), 9.42 (d, J = 1.2 Hz, 1H), 9.06 (t, J = 6.2 Hz, 1H), 8.45 (d, J = 6.1 Hz, 1H), 7.76 (dd, J = 6.1, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.35 - 7.29 (m, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.19 (dd, J = 1.9, 1.0 Hz, 1H), 4.56 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.65 (s, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.37 (s, 2H), 1.62 (t, J = 7.0 Hz, 2H), 1.57 - 1.42 (m, 8H). ESI-MS m / z: 443.1 [M+H] + .

[0578] Example 95: Synthesis of N-((2-((2-azaspiro[4.5]dec-2-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 95)

[0579] Compound 95 was prepared as a white solid from intermediate 3-2 and 2- azaspiro[4.5]decane using the method described in compound 3.

[0580] 1 H NMR (500 MHz, DMSO-d6) δ 10.88 (d, J = 2.0 Hz, 1H), 9.43 (d, J = 1.2 Hz, 1H), 9.05 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.75 (dd, J = 6.1, 1.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.19 (dd, J = 2.0, 1.0 Hz, 1H), 4.56 (d, J = 6.3 Hz, 2H), 4.13 (s, 3H), 3.62 (s, 2H), 2.50 - 2.48 (m, 2H), 2.29 (s, 2H), 1.49 (t, J = 6.9 Hz, 2H), 1.42 - 1.26 (m, 10H). ESI-MS m / z: 457.0 [M+H] + .

[0581] Example 96: Synthesis of N-((2-((7-azaspiro[3.5]nonan-7-yl)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 96)

[0582] Compound 96 was prepared as a white solid from intermediate 3-2 and 7- azaspiro[3.5]nonane hydrochloride using the method described in compound 3.

[0583] 1H NMR (500 MHz, DMSO-d6) δ 10.88 (d, J = 1.9 Hz, 1H), 9.43 (s, 1H), 9.05 (t, J = 6.3 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.75 (dd, J = 6.1, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.98 (dd, J = 8.1, 1.5 Hz, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 4.13 (s, 3H), 3.50 (s, 2H), 2.25 (s, 4H), 1.86 - 1.74 (m, 2H), 1.66 (t, J = 7.6 Hz, 4H), 1.51 (t, J = 5.4 Hz, 4H). ESI-MS m / z: 443.1 [M+H] + .

[0584] Example 97: N-((2-(((Cyclobutylmethyl)amino)methyl)-5-fluoro-lH-indol-6-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 97)

[0585] Compound 97 was prepared as a white solid from Intermediate A2 and Intermediate B3 using the method described in Compound 3. ESI-MS m / z: 421.1 [M+H] + .

[0586] Example 99: N-((6-(((Cyclobutylmethyl)amino)methyl)-l-methoxyisoquinolin-3-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 99)

[0587] Compound 99 was prepared as a white solid from Intermediate A2 and Intermediate B4 using the method described in Compound 3. ESI-MS m / z: 445.1 [M+H] + .

[0588] Example 100: N-((6-(((Cyclobutylmethyl)amino)methyl)-l-methylisoquinolin-3-yl)methyl)-l- methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 100)

[0589] Compound 100 was prepared as a white solid from Intermediate A2 and Intermediate B5 using the method described in Compound 3. ESI-MS m / z: 429.1 [M+H] + .

[0590] Example 108: 7-bromo-N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6- yl)methyl)-l-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 108)

[0591] Compound 108 was prepared as a white solid from intermediate Al 9 and intermediate Bl using the method described in Compound 3. ESI-MS m / z: 481.3 [M+H] + .

[0592] Example 110: N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l- methyl-7-(methylamino)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 110)

[0593] Intermediate 110-1 was prepared as a yellow oily liquid from intermediate A20 and intermediate Bl using the method described in Compound 3. ESI-MS m / z: 582.1 [M+H] + .

[0594] Intermediate 110-1 (95.0 mg, 163.31 pmol) was dissolved in DCM (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. TLC detection showed that the starting material was completely consumed. The reaction solution was concentrated under reduced pressure, neutralized with a saturated sodium bicarbonate solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was separated and purified by pre-HPLC to obtain Compound 110 (32.0 mg, yield 45%) as a white solid. ESI-MS m / z: 432.1 [M+H] + .

[0595] Example 115: N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l- methyl-7-(methyl-d3)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 115)

[0596] Compound 115 was prepared as a white solid from intermediate A21 and intermediate Bl using the method described in Compound 3. ESI-MS m / z: 420.1 [M+H] + .

[0597] Example 116: N-((2-(((cyclobutylmethyl)amino)methyl)-lH-indol-6-yl)methyl)-l,7- bis(methyl-d3)-lH-pyrazolo[4,3-c]pyridine-3-carboxamide (Compound 116)

[0598] Using the method described in compound 115, deuterated iodomethane was used to replace iodomethane to prepare compound 116 as a white solid. ESI-MS m / z: 423.1 [M+H] + .

[0599] Biological evaluation

[0600] Test METTL3 enzyme activity detection

[0601] In this experiment, the activity of the compound was detected by HTRF method. HTRF technology includes two technologies of fluorescence resonance energy transfer and time-resolved fluorescence. Eu 3+ labeled antibody (HTRF donor) recognizes the corresponding labeled protein by recognizing the affinity tag, glutathione S-transferase (GST), and biotinylated RNA is labeled with biotin-streptavidin. The corresponding labeled RNA is recognized by the interaction of biotin-streptavidin and XL665-conjugated streptavidin. When biomolecules interact, fluorescence resonance energy transfer occurs between the acceptor and the donor. There are two excitation lights of 620 nm and 665 nm, and when there is no interaction, there is only one excitation light of 620 nm. In this experiment, YTHDF2 protein with GST tag can specifically recognize biotinylated methylated single-stranded fragment RNA, thereby generating a light signal of 665 nm. The strength of the light signal is related to the degree of RNA methylation; methyltransferase METTL3 can methylate the substrate fragment RNA, and the inhibitory effect of the compound on METTL3 enzyme activity can be achieved by detecting the degree of RNA methylation, thereby reflecting the inhibitory effect of the compound on METTL3

[0602] 1.1 Reagents and instruments

[0603] Instrument: multifunctional enzyme label instrument (Tecan Spark cyto), TopSeal TM A films (part number 6005185), White optiplate TM 384 (part number 6007299);

[0604] Reagent: HTRF donor Eu 3+The HTRF donor antibody and the HTRF acceptor XL665-conjugated streptavidin were both purchased from PerkinElmer Shanghai; the enzyme reaction substrate 5'-biotinylated single strand (ss) RNA (5'-AAGAACCGGACUAAGCU-3') was purchased from Guangzhou RiboBio Biotech Co., Ltd.; the recombinant METTL3 / METTL14 complex and the recombinant YTHDF2 were both purchased from Shanghai MerMade Shanghai Biotech Center; the methyl donor SAM (article number A7007) was purchased from Sigma-Aldrich.

[0605] 1.2 Test method

[0606] (1) Prepare Reaction buffer, dilute METTL3 / METTL14 enzyme, SAM, inhibitors and RNA fragments with Reaction buffer;

[0607] (2) Add the following reagents to the 384-well plate white plate in turn: 5 μL of inhibitor (4x) or Assay Buffer, 5 μL of METTL3 / METTL14 enzyme (4x), incubate at room temperature for 20 min, then add the following reagents in turn: 5 μL of RNA fragments (4x), 5 μL of SAM (4x);

[0608] (3) Seal the microplate in the dark and place it at room temperature for 60 min;

[0609] (4) Prepare Detection Buffer, prepare SA-XL665 Beads and YTHDF2 enzyme with Detection Buffer; add 10 μL of (4x) SA-XL665 Beads and 10 μL of (4x) YTHDF2 enzyme, seal and incubate in the dark for 60 min;

[0610] (5) Read using the multifunctional enzyme reader Tecan. Two sets of holes were set for each experiment, and a blank control group was set.

[0611] 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)}

[0612] The inhibition rate (%) is taken as the vertical coordinate, the compound concentration is taken as the horizontal coordinate, the competition inhibition curve is drawn by using Graphpad prism software, and the IC 50 .

[0613] The IC value of the compound of the embodiment for METTL3 enzymatic inhibition is shown in Table 2. 50

[0614] Table 2

[0615] Note: "+" indicates 1.0 μM≤IC 50 ≤10 μM; "++" indicates 0.2 μM≤IC 50 <1.0 μM; "+++" indicates IC 50 <0.2 μM.

[0616] Conclusion: As can be seen from Table 2, the compound of the present application has obvious inhibitory effect on the activity of METTL3 enzyme.

[0617] The technical features of the above-described embodiments can be combined arbitrarily, and in order to make the description simple, all possible combinations of the technical features in the above-described embodiments are not described, however, as long as the combinations of the technical features do not contradict, they should be considered as the scope of the present disclosure.

[0618] The above-described embodiments only express several implementation manners of the present application, facilitate specific and detailed understanding of the technical solutions of the present application, but should not be understood as a limitation on the patent protection scope of the application. It should be noted that for ordinary skilled persons in the art, on the premise of not departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the protection scope of the present application. It should be understood that the technical solutions obtained by the skilled person in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present application are all within the protection scope of the appended claims of the present application. Therefore, the patent protection scope of the present application should be based on the contents of the appended claims, and the description can be used to explain the contents of the claims.​

Claims

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): wherein, 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 is independently selected from C or N; X 4 , X 5 , X 6 and X 7 are each independently selected from N or CR A1 ; X 8 and X 9 are each independently selected from C or N; wherein, 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 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, hydroxy-substituted 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 , -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 are each independently selected from H, -NH2, -OH, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; or, R A1b and R A1c with the N atom to which they are attached form a 4- to 9-membered heterocycloalkyl group, or R A1b and R A1c with the N atom to which they are attached and a further heteroatom selected from O, N or S form a 4- to 9-membered heterocycloalkyl group, wherein said 4- to 9-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, optionally, R A1b and R A1c with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, or R A1b and R A1c with the N atom to which they are attached and a further heteroatom selected from O, N or S form a 4- to 6-membered heterocycloalkyl group; or, R A2b and R A2c with the N atom to which they are attached form a 4- to 9-membered heterocycloalkyl group, or R A2b and R A2c with the N atom to which they are attached and a further heteroatom selected from O, N or S form a 4- to 9-membered heterocycloalkyl group, wherein said 4- to 9-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, optionally, R A2b and R A2c with the N atom to which they are attached form a 4- to 9-membered heterocycloalkyl group, or R A2b and R A2c with the N atom to which they are attached and a further heteroatom selected from O, N or S form a 4- to 9-membered heterocycloalkyl group; R A1d and R A2d are each independently selected from H or C 1-3 alkyl; Said L is selected from or 5- to 6-membered heteroarylene, when L is selected from at the time, it passes through the carbonyl side with connected, each of said 5- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl; wherein, R L1 selected from H, C 1-6 alkyl or C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; 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, S; wherein the ring carbon atoms of the 5- to 10-membered heteroarylene are optionally oxidized to form carbonyl; the C 6-10 arylene or 5- to 6-membered heteroarylene is independently substituted with 1-4 substituents independently selected from H, halogen, -OH, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C l-6 haloalkyl, hydroxy-substituted 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 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 containing 1 to 3 heteroatoms selected from N, O, S; R B1a , R B1b , and R B1c are each independently selected from H, -NH2, -OH, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; or, R B1b and R B1c with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, or R B1b and R B1c with the N atom to which they are attached and a further heteroatom selected from O, N or S form a 4- to 6-membered heterocycloalkyl group, wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl; 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 with the atom to which they are attached forming a carbonyl (=0), thiocarbonyl (=S), C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl with a heteroatom selected from O, N or S, each of said cycloalkyl or heterocyclyl being optionally substituted with 1-3 substituents independently selected from halogen, C 1-4 alkyl or C 1-4 haloalkyl; R 2a with R 2b optionally with the atom to which it is attached forming a carbonyl (=0), thiocarbonyl (=S), C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl with another heteroatom selected from O, N or S, each of said cycloalkyl or heterocyclyl being optionally substituted with 1-3 substituents independently selected from halogen, C 1-4 alkyl or C 1-4 haloalkyl; R 3a and R 3b each independently is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl or wherein said C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, each optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl; or, R 3a and R 3b form, together with the N atom to which they are attached, a 3- to 12-membered heterocycloalkyl group, or R 3a and R 3b form, together with the N atom to which they are attached and a further heteroatom selected from O, N or S, a 3- to 12-membered heterocycloalkyl group, wherein said 3- to 12-membered heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from H, halogen, -OH, =0, cyano, nitro, -NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy or C 3-8 cycloalkyl; Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 3-12 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 3-12 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 1-6 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 1-6 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 1-6 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 1-6 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 1-6 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 1-6 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C 3-8 Cycloalkyl or 3- to 12-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; said phenyl, C The fused bicyclic compound or pharmaceutically acceptable salt thereof according to claim 1, wherein, selected from the group consisting of m is selected from 0, 1, 2, 3 or 4. The fused bicyclic compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, 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 independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, or, R A1b and R A1c together with the N atom to which they are attached form a 4- to 9- membered heterocycloalkyl group, optionally, R A1b and R A1c together with the N atom to which they are attached form a 4- to 6- membered heterocycloalkyl group. The fused bicyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, R A2 independently selected from H or C 1-6 alkyl; said C 1-6 each Rais independently selected from H, D, or halogen. The fused bicyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, L is selected from The fused bicyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein, Ring B is selected from Ring B is attached via the * side to R 1a , R 1b substituted carbon; wherein, n is selected from 0, 1, 2, 3 or 4; R B1 R A1 . The fused bicyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein, R 3a and R 3b each independently is selected from H, methyl, ethyl, propyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, or wherein, each of the methyl, ethyl, propyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl is optionally substituted with 1-3 substituents independently selected from H, F, Cl, Br, I, -OH, =O, cyano, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy or cyclopropyl; Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetanyl, azetidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, cyclopropylcyclopentyl, cyclopentylcyclobutyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopentyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinazetidinylspirooxetanyl, azetidinylspirooxetanyl, azetidinylspirooxetanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.3.2]decanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.3]undecanyl, adamantyl, when substituted, optionally further substituted with 1-3 selected from H, halo, -OH, =0, cyano, nitro, -NH2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or C 3-6 cycloalkyl. The fused bicyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, 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, optionally further substituted with 1-3 selected from H, halo, -OH, =0, cyano, nitro, -NH2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or C 3-6 cycloalkyl. A pharmaceutical composition comprising the fused bicyclic compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated isotope, solvate, prodrug, metabolite, co-crystal thereof of any one of claims 1-8, and a pharmaceutically acceptable carrier. Use of the fused bicyclic compound or a pharmaceutically acceptable salt thereof of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating and / or preventing a disease associated with or mediated by METTL3 activity. Optionally, the disease is selected from cancer, autoimmune disease, inflammatory disease 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, glioblastoma, 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 or nasopharyngeal carcinoma; more further optionally, the cancer is acute myeloid leukemia. Use of the fused bicyclic compound or a pharmaceutically acceptable salt thereof of any one of claims 1-8 or the pharmaceutical composition of claim 9 in combination with one or more antitumor drugs in the preparation of a medicament for treating and / or preventing a cancer associated with or mediated by METTL3 activity. Optionally, the antitumor drug is selected from one or more of alkylating agents, platinum complexing 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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